Characterization of adnexal lesions using photoacoustic imaging to improve sonographic O-RADS risk assessment.

OBJECTIVE: To assess the impact of photoacoustic imaging (PAI) on the assessment of ovarian/adnexal lesion(s) of different risk categories using the sonographic ovarian-adnexal imaging-reporting-data system (O-RADS) in women undergoing planned oophorectomy. METHOD: This prospective study enrolled women with ovarian/adnexal lesion(s) suggestive of malignancy referred for oophorectomy. Participants underwent clinical ultrasound (US) examination followed by coregistered US and PAI prior to oophorectomy. Each ovarian/adnexal lesion was graded by two radiologists using the US O-RADS scale. PAI was used to compute relative total hemoglobin concentration (rHbT) and blood oxygenation saturation (%sO2 ) colormaps in the region of interest. Lesions were categorized by histopathology into malignant ovarian/adnexal lesion, malignant Fallopian tube only and several benign categories, in order to assess the impact of incorporating PAI in the assessment of risk of malignancy with O-RADS. Malignant and benign histologic groups were compared with respect to rHbT and %sO2 and logistic regression models were developed based on tumor marker CA125 alone, US-based O-RADS alone, PAI-based rHbT with %sO2 , and the combination of CA125, O-RADS, rHbT and %sO2. Areas under the receiver-operating-characteristics curve (AUC) were used to compare the diagnostic performance of the models. RESULTS: There were 93 lesions identified on imaging among 68 women (mean age, 52 (range, 21-79) years). Surgical pathology revealed 14 patients with malignant ovarian/adnexal lesion, two with malignant Fallopian tube only and 52 with benign findings. rHbT was significantly higher in malignant compared with benign lesions. %sO2 was lower in malignant lesions, but the difference was not statistically significant for all benign categories. Feature analysis revealed that rHbT, CA125, O-RADS and %sO2 were the most important predictors of malignancy. Logistic regression models revealed an AUC of 0.789 (95% CI, 0.626-0.953) for CA125 alone, AUC of 0.857 (95% CI, 0.733-0.981) for O-RADS only, AUC of 0.883 (95% CI, 0.760-1) for CA125 and O-RADS and an AUC of 0.900 (95% CI, 0.815-0.985) for rHbT and %sO2 in the prediction of malignancy. A model utilizing all four predictors (CA125, O-RADS, rHbT and %sO2 ) achieved superior performance, with an AUC of 0.970 (95% CI, 0.932-1), sensitivity of 100% and specificity of 82%. CONCLUSIONS: Incorporating the additional information provided by PAI-derived rHbT and %sO2 improves significantly the performance of US-based O-RADS in the diagnosis of adnexal lesions. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

CT-derived textural analysis parameters discriminate high-attenuation renal cysts from solid renal neoplasms.

AIM: To assess the utility of textural features on computed tomography (CT) to differentiate high-attenuation cysts from solid renal neoplasms among indeterminate renal lesions detected incidentally on CT. MATERIALS AND METHODS: Patients were included if they had an indeterminate renal lesion on CT that was subsequently characterised on ultrasound or magnetic resonance imaging (MRI). Up to three lesions per patient were included if they had a size ≥10 mm and density of 20-70 HU on unenhanced CT or any single phase of contrast-enhanced CT. Cases were categorised as benign or most likely benign cysts (Bosniak II and IIF) versus indeterminate (Bosniak III), mixed solid and cystic (Bosniak IV), or solid renal lesions. A random forest model was generated using 95 textural parameters and four clinical parameters for each lesion. RESULTS: Two hundred and thirty-four patients were included who had a total of 278 lesions. Of these, 193 (69%) were benign or most likely benign cysts and 85 (31%) were indeterminate, mixed cystic and solid, or solid renal lesions. The random forest model had an area under the curve of 0.71 (95% confidence interval [CI]: 0.65, 0.78), with a sensitivity and specificity of 81.2% and 38.9%, respectively. CONCLUSION: A multivariate model including textural and clinical parameters had moderate overall performance for discriminating benign or likely benign cysts from indeterminate, mixed solid and cystic, or solid renal lesions. This study serves as a proof of concept and may reduce the need for further follow-up by characterising a significant portion of indeterminate lesions on CT as benign.

Changes in Disease Behaviour and Location in Patients With Crohn's Disease After Seven Years of Follow-Up: A Danish Population-based Inception Cohort.

BACKGROUND AND AIM: Crohn's disease [CD] is a progressive inflammatory bowel disease that can lead to complications such as strictures or penetrating disease, and ultimately surgery. Few population-based studies have investigated the predictors for disease progression and surgery in CD according to the Montreal classification. We aimed to identify clinical predictors associated with complicated CD in a Danish population-based inception cohort during the biologic era. METHODS: All incident patients with CD in a well-defined Copenhagen area, between 2003 and 2004, were followed prospectively until 2011. Disease progression was defined as the development of bowel stricture [B2] or penetrating disease [B3] in patients initially diagnosed with non-stricturing/non-penetrating disease [B1]. Associations between disease progression and/or resection, and multiple covariates, were investigated by Cox regression analyses. RESULTS: In total, 213 CD patients were followed. A total of 177 [83%] patients had B1 at diagnosis. Patients who changed location had increased risk of disease progression (hazard ratio [HR] = 3.1, 95% CI: 1.12,8.52). Biologic treatment was associated with lower risk of change in location [HR = 0.3, 95% CI: 0.1-0.7]. Colonic involvement [L2 or L3 vs L1] was associated with a lower risk of surgery (HR = 0.34/0.22, 95% CI: [0.13,0.86]/[0.08,0.60]). All CD patients who progressed in behaviour or changed location had an increased risk of surgery [p < 0.05]. CONCLUSIONS: This population-based inception cohort study demonstrates that changes in disease location or behaviour in patients with CD increase their risk of resection. Our findings highlight the protective effect of biologic treatment with regard to change in disease location, which might ultimately improve the disease course for CD patients.

A validated web-based tool to display individualised Crohn's disease predicted outcomes based on clinical, serologic and genetic variables.

BACKGROUND: Early treatment for Crohn's disease (CD) with immunomodulators and/or anti-TNF agents improves outcomes in comparison to a slower 'step up' algorithm. However, there remains a limited ability to identify those who would benefit most from early intensive therapy. AIM: To develop a validated, individualised, web-based tool for patients and clinicians to visualise individualised risks for developing Crohn's disease complications. METHODS: A well-characterised cohort of adult patients with CD was analysed. Available data included: demographics; clinical characteristics; serologic immune responses; NOD2 status; time from diagnosis to complication; and medication exposure. Cox proportional analyses were performed to model the probability of developing a CD complication over time. The Cox model was validated externally in two independent CD cohorts. Using system dynamics analysis (SDA), these results were transformed into a simple graphical web-based display to show patients their individualised probability of developing a complication over a 3-year period. RESULTS: Two hundered and forty three CD patients were included in the final model of which 142 experienced a complication. Significant variables in the multivariate Cox model included small bowel disease (HR 2.12, CI 1.05-4.29), left colonic disease (HR 0.73, CI 0.49-1.09), perianal disease (HR 4.12, CI 1.01-16.88), ASCA (HR 1.35, CI 1.16-1.58), Cbir (HR 1.29, CI 1.07-1.55), ANCA (HR 0.77, CI 0.62-0.95), and the NOD2 frameshift mutation/SNP13 (HR 2.13, CI 1.33-3.40). The Harrell's C (concordance index for predictive accuracy of the model) = 0.73. When applied to the two external validation cohorts (adult n = 109, pediatric n = 392), the concordance index was 0.73 and 0.75, respectively, for adult and pediatric patients. CONCLUSIONS: A validated, web-based tool has been developed to display an individualised predicted outcome for adult patients with Crohn's disease based on clinical, serologic and genetic variables. This tool can be used to help providers and patients make personalised decisions about treatment options.

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.

Clinical and demographic characteristics predictive of treatment outcomes for certolizumab pegol in moderate to severe Crohn's disease: analyses from the 7-year PRECiSE 3 study.

BACKGROUND: Clinical factors were previously identified as predictors of short-term treatment efficacy in Crohn's disease (CD). The PRECiSE 3 (P3) 7-year trial provides an opportunity to study predictors of short- and long-term clinical remission among CD patients treated with certolizumab pegol (CZP). AIM: To identify factors that influence long-term remission of CD with CZP treatment. METHODS: Patients who had completed placebo-controlled studies (PRECiSE 1/PRECiSE 2, P1/P2) enrolled in P3 and received open-label CZP 400 mg every 4 weeks up to 7 years. Baseline predictors included, but were not limited to, smoking status, disease duration, prior inflammatory bowel disease (IBD) surgery, Harvey-Bradshaw Index (HBI), albumin, haematocrit and CZP exposure; association with time to initial remission (HBI ≤4) was tested for patients who received CZP in P1/P2; time to loss of remission/frequency of maintenance of remission was also tested. Univariate analyses and multivariate Cox or logistic regression models were used. RESULTS: Predictors for initial remission (N = 377) included age, haematocrit, prior IBD surgery and entry HBI (P < 0.05 for all). Predictors for loss of remission (N = 437) included HBI, serum albumin concentration, haematocrit, smoking status and exposure. Predictors of maintenance of remission (N = 437) included haematocrit, IBD surgery, HBI, disease duration, serum albumin concentration and exposure. Significant predictors were confirmed with stepwise multivariate regression models. CONCLUSIONS: These analyses identified several influential parameters for short-and long-term remission of Crohn's disease with certolizumab pegol treatment. The data yield valuable hypotheses regarding factors that influence certolizumab pegol treatment. More investigation is needed. (ClinicalTrials.gov identifier NCT00552058).

Automatic delineation of tumor volumes by co-segmentation of combined PET/MR data.

Combined PET/MRI may be highly beneficial for radiotherapy treatment planning in terms of tumor delineation and characterization. To standardize tumor volume delineation, an automatic algorithm for the co-segmentation of head and neck (HN) tumors based on PET/MR data was developed. Ten HN patient datasets acquired in a combined PET/MR system were available for this study. The proposed algorithm uses both the anatomical T2-weighted MR and FDG-PET data. For both imaging modalities tumor probability maps were derived, assigning each voxel a probability of being cancerous based on its signal intensity. A combination of these maps was subsequently segmented using a threshold level set algorithm. To validate the method, tumor delineations from three radiation oncologists were available. Inter-observer variabilities and variabilities between the algorithm and each observer were quantified by means of the Dice similarity index and a distance measure. Inter-observer variabilities and variabilities between observers and algorithm were found to be comparable, suggesting that the proposed algorithm is adequate for PET/MR co-segmentation. Moreover, taking into account combined PET/MR data resulted in more consistent tumor delineations compared to MR information only.

Systematic review: The safety and efficacy of hyperbaric oxygen therapy for inflammatory bowel disease.

BACKGROUND: Hyperbaric oxygen therapy (HBOT) provides 100% oxygen under pressure, which increases tissue oxygen levels, relieves hypoxia and alters inflammatory pathways. Although there is experience using HBOT in Crohn's disease and ulcerative colitis, the safety and overall efficacy of HBOT in inflammatory bowel disease (IBD) is unknown. AIM: To quantify the safety and efficacy of HBOT for Crohn's disease (CD) and ulcerative colitis (UC). The rate of adverse events with HBOT for IBD was compared to the expected rate of adverse events with HBOT. METHODS: MEDLINE, EMBASE, Cochrane Collaboration and Web of Knowledge were systematically searched using the PRISMA standards for systematic reviews. Seventeen studies involving 613 patients (286 CD, 327 UC) were included. RESULTS: The overall response rate was 86% (85% CD, 88% UC). The overall response rate for perineal CD was 88% (18/40 complete healing, 17/40 partial healing). Of the 40 UC patients with endoscopic follow-up reported, the overall response rate to HBOT was 100%. During the 8924 treatments, there were a total of nine adverse events, six of which were serious. The rate of adverse events with HBOT in IBD is lower than that seen when utilising HBOT for other indications (P < 0.01). The risk of bias across studies was high. CONCLUSIONS: Hyperbaric oxygen therapy is a relatively safe and potentially efficacious treatment option for IBD patients. To understand the true benefit of HBOT in IBD, well-controlled, blinded, randomised trials are needed for both Crohn's disease and ulcerative colitis.

Review article: integrating budesonide-MMX into treatment algorithms for mild-to-moderate ulcerative colitis.

BACKGROUND: 5-Aminosalicylates (5-ASA) are first-line treatment for mild-moderately active ulcerative colitis (UC). When 5-ASAs fail, systemic corticosteroids have been the standard next step. Due to the significant side effect profile of systemic corticosteroids, alternative options in the treatment algorithm after 5-ASA failures are needed. Budesonide-Multi-Matrix System (MMX) is a novel oral formulation of budesonide that uses colonic release MMX technology to extend release of the drug to the colon. Now that budesonide-MMX has been approved for use in some countries, and pending in others we need to understand its position in the treatment algorithm for UC. AIM: To review the available literature for budesonide-MMX and incorporate it into the treatment algorithm for mild-moderate UC. METHODS: The available efficacy and safety literature regarding budesonide-MMX was reviewed, and compared to 5-ASAs and systemic corticosteroids. RESULTS: In two large studies referred to as CORE (Colonic Release Budesonide trial), budesonide-MMX 9 mg daily was significantly more effective in achieving a combined end point of clinical and endoscopic remission than placebo in patients with mild-moderately active UC. Safety data are reassuring, with no clinically relevant differences between budesonide-MMX and placebo, including steroid-related side effects. CONCLUSIONS: Budesonide-MMX 9 mg daily is an effective and safe treatment for induction in patients with mild-moderately active UC. At the current time, it should be considered in patients after 5-ASA failure and before systemic corticosteroids. Data are still needed to understand its role and dose beyond 8 weeks, and if it should be considered first line before 5-ASAs.

NAD+ and nicotinamide: sex differences in cerebral ischemia.

BACKGROUND: Previous literature suggests that cell death pathways activated after cerebral ischemia differ between the sexes. While caspase-dependent mechanisms predominate in the female brain, caspase-independent cell death induced by the activation of poly(ADP-ribose) polymerase (PARP) predominates in the male brain. PARP-1 gene deletion decreases infarction volume in the male brain, but paradoxically increases damage in PARP-1 knockout females. PURPOSE: This study examined stroke-induced changes in NAD+, a key energy molecule involved in PARP-1 activation in both sexes. METHODS: Mice were subjected to middle cerebral artery occlusion and NAD+ levels were assessed. Caspase-3 activity and nuclear translocation were assessed 6h after ischemia. In additional cohorts, Nicotinamide (500 mg/kg i.p.) a precursor of NAD+ or vehicle was administered and infarction volume was measured 24h after ischemia. RESULTS: Males have higher baseline NAD+ levels than females. Significant stroke-induced NAD+ depletion occurred in males and ovariectomized females but not in intact females. PARP-1 deletion prevented the stroke-induced loss in NAD+ in males, but worsened NAD+ loss in PARP-1 deficient females. Preventing NAD+ loss with nicotinamide reduced infarct in wild-type males and PARP-1 knockout mice of both sexes, with no effect in WT females. Caspase-3 activity was significantly increased in PARP-1 knockout females compared to males and wild-type females, this was reversed with nicotinamide. CONCLUSIONS: Sex differences exist in baseline and stroke-induced NAD+ levels. Nicotinamide protected males and PARP knockout mice, but had minimal effects in the wild-type female brain. This may be secondary to differences in energy metabolism between the sexes.

Setting priorities for comparative effectiveness research in inflammatory bowel disease: results of an international provider survey, expert RAND panel, and patient focus groups.

BACKGROUND: Comparative effectiveness research (CER) is an emerging field that compares the relative effectiveness of alternative strategies to prevent, diagnose, or treat patients who are typical of day-to-day practice. We developed a priority list of CER topics for inflammatory bowel disease (IBD). METHODS: Following the Institute of Medicine's approach, we developed and administered a survey to gastroenterologists asking for important CER topics in IBD. Two patient focus groups were convened to solicit additional CER studies. CER topics were presented to the expert panel using the RAND/UCLA methodology. Following initial ratings, the panel met to discuss and re-rate priorities. The top 10 CER topics were identified using a point-allocation system. RESULTS: Responses were collated into 234 CER topics across 21 categories, of which 87 were prioritized for discussion and re-rated. Disagreement regarding priorities was observed in 5 of 87 studies. We utilized a point-allocation system to prioritize the top-10 CER topics. These related to comparing the effectiveness of: biomarkers in IBD; withdrawal of anti-tumor necrosis factor (TNF) or immunomodulators for Crohn's disease in remission; mucosal healing as an endpoint of treatment; infliximab levels versus standard infliximab dosing; anti-TNF monotherapy versus combination therapy in patients failing thiopurines; safety of long-term treatment options; anti-TNF versus thiopurines for prevention of postoperative recurrence; and treatment options for steroid-refractory UC. CONCLUSIONS: We systematically developed a list of high-priority IBD topics for CER based on a survey of gastroenterologists, expert review, and patient input. This list may guide IBD research toward the most important CER studies.

Review article: explaining risks of inflammatory bowel disease therapy to patients.

BACKGROUND: Medical treatment for inflammatory bowel disease (IBD) has advanced significantly over the past decade, but it is important to communicate effectively the balance of benefits and risks of therapy to patients to facilitate informed medical decisions. AIM: To review the available data describing the risk of side effects of IBD medications and to describe effective methods for communicating risk. METHODS: To identify relevant articles for this review, a PubMed search was conducted using relevant key words and phrases. In addition, reference lists from identified manuscripts were searched and recent abstracts from National meetings were reviewed. RESULTS: The steroid-sparing medications used for the treatment of IBD all carry risks of both common and rare adverse events. Trade-offs need to be made between the risks of these medications vs. the risks of poorly treated disease and corticosteroids. There has been significant research on how best to present risk data to patients, which is summarized in this review. CONCLUSIONS: To ensure that our patients understand their choices and feel comfortable with their treatment, we need to communicate risk data to patients clearly. Patients comprehend absolute numbers better than relative risk, and when available, pictorial representations of data are preferred over solely presenting numerical outcomes.

NAD+ depletion or PAR polymer formation: which plays the role of executioner in ischaemic cell death?

Multiple cell death pathways are activated in cerebral ischaemia. Much of the initial injury, especially in the core of the infarct where cerebral blood flow is severely reduced, is necrotic and secondary to severe energy failure. However, there is considerable evidence that delayed cell death continues for several days, primarily in the penumbral region. As reperfusion therapies grow in number and effectiveness, restoration of blood flow early after injury may lead to a shift towards apoptosis. It is important to elucidate what are the key mediators of apoptotic cell death after stroke, as inhibition of apoptosis may have therapeutic implications. There are two well described pathways that lead to apoptotic cell death; the caspase pathway and the more recently described caspase-independent pathway triggered by poly-ADP-ribose polymers (PARP) activation. Caspase-induced cell death is initiated by release of mitochondrial cytochrome c, formation of the cytosolic apoptosome, and activation of endonucleases leading to a multitude of small randomly cleaved DNA fragments. In contrast caspase-independent cell death is secondary to activation of apoptosis inducing factor (AIF). Mitochondrial AIF translocates to the nucleus, where it induces peripheral chromatin condensation, as well as characteristic high-molecular-weight (50 kbp) DNA fragmentation. Although caspase-independent cell death has been recognized for some time and is known to contribute to ischaemic injury, the upstream triggering events leading to activation of this pathway remain unclear. The two major theories are that ischaemia leads to nicotinamide adenine dinucleotide (NAD+) depletion and subsequent energy failure, or alternatively that cell death is directly triggered by a pro-apoptotic factor produced by activation of the DNA repair enzyme PARP. PARP activation is robust in the ischaemic brain producing variable lengths of poly-ADP-ribose (PAR) polymers as byproducts of PARP activation. PAR polymers may be directly toxic by triggering mitochondrial AIF release independently of NAD+ depletion. Recently, sex differences have been discovered that illustrate the importance of understanding these molecular pathways, especially as new therapeutics targeting apoptotic cell death are developed. Cell death in females proceeds primarily via caspase activation whereas caspase-independent mechanisms triggered by the activation of PARP predominate in the male brain. This review summarizes the current literature in an attempt to clarify the roles of NAD+ and PAR polymers in caspase-independent cell death, and discuss sex specific cell death to provide an example of the possible importance of these downstream mediators.

Cyberknife stereotactic body radiation therapy for nonresectable tumors of the liver: preliminary results.

PURPOSE: Stereotactic body radiation therapy (SBRT) has emerged as a treatment option for local tumor control of primary and secondary malignancies of the liver. We report on our updated experience with SBRT in patients with non-resectable tumors of the liver. METHODS: Our first 17 consecutive patients (mean age 58.1 years) receiving SBRT for HCC (n = 6), IHC (n = 3), and LM (n = 8) are presented. Mean radiation dose was 34 Gy delivered over 1-3 fractions. RESULTS: Treated patients had a mean decrease in maximum pretreatment tumor diameter from 6.9 +/- 4.6 cm to 5.0 +/- 2.1 cm at three months after treatment (P < .05). The mean total tumor volume reduction was 44% at six months (P < .05). 82% of all patients (14/17) achieved local control with a median follow-up of 8 months. 100% of patients with HCC (n = 6) achieved local control. Patients with surgically placed fiducial markers had no complications related to marker placement. CONCLUSION: Our preliminary results showed that SBRT is a safe and effective local treatment modality in selected patients with liver malignancies with minimal adverse events. Further studies are needed to define its role in the management of these malignancies.

Modelling dysplasia detection in ulcerative colitis: clinical implications of surveillance intensity.

BACKGROUND: Endoscopic surveillance of chronic colitis uses random biopsies to find dysplastic fields. Enhanced endoscopic methods are more sensitive for dysplasia detection, but their specificity for colorectal cancer risk is unknown. AIMS: To develop a mathematical model of the sensitivity of random biopsy surveillance, and determine the implications of negative, a single positive, or multiple positive biopsies for dysplasia, and compare the detection threshold to that detectable by enhanced endoscopy. METHODS: Using mathematical modelling, we calculated the confidence level with which dysplasia can be excluded, the dysplastic field size detection threshold, the predicted area of a dysplastic field, and the number of biopsies needed for a given dysplasia detection threshold and confidence level. RESULTS: 32 random biopsies provide only 80% confidence that dysplasia involving > or =5% of the colon can be detected. When a single biopsy of 18 is dysplastic, this predicts a dysplastic area (89 cm(2)) several orders of magnitude greater than dysplastic fields that are readily detectable by enhanced endoscopy (1 cm diameter), and the predicted field size increases rapidly with multiple positive biopsies. CONCLUSIONS: Random biopsy surveillance is sufficiently sensitive to detect large dysplastic fields with significant colorectal cancer risk. Enhanced endoscopy can detect much smaller dysplastic fields, but these have unknown (perhaps much lower) colorectal cancer risk. Small dysplastic fields should not be assumed to indicate a high colorectal cancer risk that warrants colectomy. Prospective studies are needed to define the colorectal cancer risk and optimal management of small dysplastic lesions.