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Upon entry into mammalian barrier tissues such as the intestine and the lungs, immune cells are metabolically reprogrammed by the local milieu. Increased cholesterol metabolism is a feature of tissue-resident lymphocytes in the intestinal lamina propria. Chemotactic oxysterol gradients position immune cells within microanatomical niches in mucosal tissues and also drive immune cell recruitment into the respiratory tract. Recent work provides increasing evidence of the importance of cholesterol metabolism in regulating homeostatic immune function and barrier defense during infection. Immune cell function is highly regulated by cell-autonomous cholesterol metabolism; in turn, secretion of cholesterol-derived metabolites by stromal and immune cells is crucially involved in controlling mucosal immunity via cell positioning and metabolic reprogramming. An in-depth understanding of the complex crosstalk between sterols and immune cells might facilitate the development of targeted candidate therapeutics to treat both chronic and infectious diseases. Cholesterol metabolites, particularly oxidized forms known as oxysterols, play crucial roles in modulating immune and metabolic processes across various tissues. Concentrations of local cholesterol and its metabolites influence tissue-specific immune responses by shaping the metabolic and spatial organization of immune cells in barrier organs like the small intestine (SI) and lungs. We explore recent molecular and cellular evidence supporting the metabolic adaptation of innate and adaptive immune cells in the SI and lung, driven by cholesterol and cholesterol metabolites. Further research should unravel the detailed molecular mechanisms and spatiotemporal adaptations involving cholesterol metabolites in distinct mucosal tissues in homeostasis or infection. We posit that pharmacological interventions targeting the generation or sensing of cholesterol metabolites might be leveraged to enhance long-term immune protection in mucosal tissues or prevent autoinflammatory states. [ABSTRACT FROM AUTHOR]

Caco-2 cells, a human colorectal adenocarcinoma cell line, are widely used to model small intestinal epithelial cells in the drug development process because they can predict drug absorption with high accuracy. However, Caco-2 cells have several issues. First, Caco-2 cells have little expression of cytochrome P450 3A4 (CYP3A4), which is a major drug-metabolizing enzyme in the human intestine. We previously developed Caco-2 cells whose expression of CYP3A4 can be controlled using doxycycline (Dox) (CYP3A4-Caco-2 cells) (Ichikawa et al., Sci. Rep, 2021). However, since the Tet-On system was used to regulate CYP3A4 expression in these cells, there was concern about drug-drug interactions. The second issue is that in the human small intestine, carboxylesterase 2 (CES2) is more highly expressed than carboxylesterase 1 (CES1), while in Caco-2 cells CES1 is more highly expressed. The third issue is the low level expression of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), a phase II drug-metabolizing enzyme. In this study, we used genome-editing technology to establish CES1 -knockout Caco-2 cells whose CYP3A4 and UGT1A1 expression can be regulated by the Tet-Off system. These cell lines would be useful in pharmaceutical researches, including intestinal toxicological studies, as an in vitro model for orally administered drugs. [Display omitted] • CES1-KO/CYP3A4 Caco-2 cells and CES1-KO/CYP3A4-UGT1A1 Caco-2 cells are established. • CES1-KO/CYP3A4 Caco-2 cells can be used to predict absorption of prodrugs metabolized by CES. • CES1-KO/CYP3A4 Caco-2 cells have the potential to predict the metabolism of orally administered drugs involving in CYP3A4 in the small intestine. • CES1-KO/CYP3A4-UGT1A1 Caco-2 cells have the potential to predict the metabolism of orally administered drugs involving in both CYP3A4 and UGT1A1 in the small intestine. [ABSTRACT FROM AUTHOR]

Older adults (≥65 yr) account for the majority of emergency laparotomies in the UK and are well characterised with reported outcomes. In contrast, there is limited knowledge on those patients that require emergency laparotomy but do not undergo surgery (NoLaps). A multicentre cohort study (n =64 UK surgical centres) recruited 750 consecutive NoLap patients (February 15th - November 15th 2021, inclusive of a 90-day follow up period). Each patient was admitted to hospital with a surgical condition treatable by an emergency laparotomy (defined by The National Emergency Laparotomy Audit (NELA) criteria), but a decision was made not to undergo surgery (NoLap). NoLap patients were predominately female (452 patients, 60%), of advanced age (median age 83.0 yr, interquartile range 77.0–88.8), frail (523 patients, 70%), and had severe comorbidity (750 patients, 100%); 99% underwent CT scanning. The commonest diagnoses were perforation (26%), small bowel obstruction (17%), and ischaemic bowel (13%). The 90-day mortality was 79% and influencing factors were >80 yr, underweight BMI, elevated serum lactate or creatinine concentration. The majority of patients died in hospital (77%), with those with ischaemic bowel dying early. For the 21% of NoLap patients that survived to 90 days, 77% returned home with increased care requirements. This study reports that the NoLap patient population present significant medical challenges because of their extreme levels of comorbidity, frailty, and physiology. Despite these complexities a fifth remained alive at 90 days. Further work is underway to explore this high-risk decision-making process. ISRCTN14556210. [ABSTRACT FROM AUTHOR]

Diacylglycerol O -acyltransferase 1 (DGAT1) is a key enzyme for fat absorption step in the enterocytes. We previously reported that DGAT1 inhibition increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in corn oil-loaded rats via protein kinase C (PKC) activation. In the present study, we investigated the mechanism with respect to the morphology and permeability of the small intestine, focusing on PKC function, and found that shortening of the intestinal villi and a decrease in the number of tdT-mediated dUTP-biotin nick-end labeling-positive cells in the tips of the villi were observed in the jejunum of DGAT1 inhibitor-treated rats loaded with corn oil. These results suggested that the tips of the villi were shed into the intestinal lumen. Next, fluorescein isothiocyanate-dextran, 110 kDa (FD-110) was administered intraduodenally to DGAT1 inhibitor-treated rats loaded with corn oil and we found that plasma FD-110 concentrations increased, indicating that the intestinal permeability to molecules with a molecular weight of approximately 110,000 (e.g., ALT and AST) increased. Taken together, the present results suggested that DGAT1 inhibitor-treatment in combination with corn oil causes ALT and AST to leak from the enterocytes into the blood by shedding the tips of the intestinal villi and increasing intestinal permeability. • DGAT1 inhibitor shortens the intestinal villi in corn oil-loaded rats. • DGAT1 inhibitor reduces the number of TUNEL-positive cells in corn oil-loaded rats. • DGAT1 inhibitor increases intestinal permeability in corn oil-loaded rats. • DGAT1 inhibitor decreases TJ-related protein mRNA levels in corn oil-loaded rats. • Plasma ALT and AST increase by shedding the villi and increasing permeability. [ABSTRACT FROM AUTHOR]

• Gut function and transit change following the initiation of ETI, measured using MRI. • Small bowel transit and small bowel response to food improves after starting ETI. • After 18 months of ETI use, colonic volume reduces. • First imaging study to find changes in gut physiology following ETI initiation. Gastrointestinal (GI) symptoms in cystic fibrosis (CF) are common and disruptive. The effect of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on the GI tract is not fully understood. The aim was to use magnetic resonance imaging (MRI) to determine if elexacaftor/tezacaftor/ivacaftor (ETI) changed GI function and transit. This was an 18 month prospective, longitudinal, observational study. We enrolled 24 people with CF aged 12 years or older to undergo MRI scans before starting ETI and 3, 6, and 18 months after starting ETI. The primary outcome measure was change in oro-caecal transit time (OCTT) at 6 and 18 months. Secondary outcome measures included change in small bowel water content (SBWC), change in the reduction in small bowel water content following a meal (DeltaSBWC) and change in total colonic volume (TCV). A total of 21 participants completed MRI scans at 6 months and 11 completed at 18 months. After 18 months of ETI, median OCTT significantly reduced, from >360 min [IQR 240->360] to 240 min [IQR 180–300] (p = 0.02, Wilcoxon signed-rank). Both SBWC and DeltaSBWC increased after starting ETI. TCV reduced significantly after 18 months (p = 0.005, Friedman). Our findings suggest an improvement in small bowel transit, small bowel response to food and a reduction in colonic volume after starting ETI. These effects may relate to CFTR activation in the small bowel. To our knowledge this is the first study to show a physiological change in GI transit and function in response to CFTR modulator use through imaging studies. [Display omitted] [ABSTRACT FROM AUTHOR]

The intestinal microbiota plays a pivotal role in digestive processes and maintains gut health and intestinal homeostasis. These functions may be compromised by increased environmental heat, which in turn reduces feed intake and gut integrity and activates the intestinal immune system. It remains unknown whether high ambient temperatures, which cause heat stress (HS) in dairy cows, disturb the eubiosis of the microbial community, and if so, to which extent the reduction in feed intake and the impairment of circulating and intestinal metabolites account for the alterations of the jejunal microbiota. To address these questions, jejunal digesta, mucosa, and plasma samples were collected from cows exposed to heat stress (HS; 28°C, temperature-humidity index [THI] = 76, n = 10), control conditions (CON; 16°C, THI = 60, n = 10), or pair-fed (PF; 16°C, THI = 60, n = 10) for 7 d. Digesta fluids were examined for pH, acetate, nonesterified fatty acids (NEFA), glucose, and lactate, and plasma samples were analyzed for glucose, lactate, BHB, triglycerides, NEFA, creatinine, and urea. The microbiota of the digesta and mucosa samples were analyzed by 16S rRNA sequencing. The α-diversity was higher in mucosa than digesta but was not affected by high ambient temperatures. However, the mucosa-associated microbiota appeared more responsive to ambient heat than the digesta microbiome. The adaptive responses under HS conditions comprised an increased mucosal abundance of Bifidobacteriaceae , Succinivibrionaceae UCG-001, Clostridia and Lactobacillus. In the digesta, HS has exerted effects on microbial abundance of Colidextribacter , and Lachnospiraceae UCG-008. Several correlations between plasma or intestinal metabolites and microbiota were elucidated, including Methanobacteriaceae correlating positively with plasma BHB and digesta glucose concentrations. Moreover, the reduction in feed intake during HS had non-negligible effects on microbial diversity and the abundance of certain taxa, underpinning the importance of nutrient supply on maintaining intestinal homeostasis. [ABSTRACT FROM AUTHOR]

Sulfasalazine needs frequent daily dosing and the administration of numerous tablets per day pose challenges to patient compliance, contributing to increased adverse effects and difficulties in disease control. These inconveniences result in less effective treatment for arthritis associated with inflammatory bowel disease i.e. ulcerative colitis etc. To improve drug bioavailability, a delayed-release mechanism that releases the drug at the colon is necessary. To develop and optimize colon-targeted controlled release bilayer tablets coated with pH-dependent polymers. The bilayer tablets containing the immediate release part and sustained release part were developed. The tablets were coated with enteric-coated with Eudragit® S-100 and l -100 to achieve release in the colon. Granule properties and tablets were evaluated. The physicochemical parameters of the tablets were evaluated including, stability study, and drug release in 0.1 N HCl (pH 1.2), pH 6.8 phosphate buffer, pH 7.4 phosphate buffer for 2, 1, and up to 24 h respectively. Radiographic imaging and in vivo pharmacokinetic studies were also done in Rabbits. The bilayer tablets containing immediate and sustained release were successfully developed for the colon targeting. The granule properties were found within the acceptable range indicating good flow properties. The physicochemical properties of the tablets were also found acceptable. The tablets did not show release in 0.1 N HCl and 6.8 phosphate buffer but drug release was found under control in the 7.4 pH buffer. Sulfasalazine coated bilayer tablets were found stable and no significant changes were observed in the stability studies. Based on the X-ray studies, the formulated tablet remained discernible in the stomach, small intestine, and colon for a duration of up to 24 h. Finally, by the 32nd hour, the tablet was no longer visible in the X-ray examination, leading to the conclusion of complete drug release. The drug concentration in plasma remained within the therapeutic range for up to 24 h in vivo. These novel formulations present substantial advantages, providing prolonged targeted drug release and reducing systemic adverse effects. The results suggest promising potential for treating arthritis in Inflammatory bowel disease (IBD) patients, offering a solution to current delivery systems. [Display omitted] [ABSTRACT FROM AUTHOR]

White-tailed antsangies (Brachytarsomys albicauda) are Madagascan rodents uncommonly kept in captivity. Hymenolepis nana is a cestode with an unusual life cycle, incorporating direct, indirect and autoinfective stages. This case series represents the first reported outbreak of H. nana cestodiasis in white-tailed antsangies, summarizing macroscopic and histological findings in four cases. On post-mortem examination (PME), numerous cysticerci were detected consistently throughout the intestinal serosa, liver, mesenteric lymphatic vasculature and mesenteric lymph nodes. Pancreatic cysticerci were observed in one case. Adult tapeworms, larvae and eggs were found only in the small intestine, and faecal egg shedding was a feature. Histopathological examination identified adult, larval and encysted cestodes within the respective gross lesions, with pulmonary, pancreatic and splenic involvement detected in a single case. The cestodes sampled on PME were identified by polymerase chain reaction and DNA sequencing, with H. nana confirmed in all cases. Visceral larva migrans was consistent throughout all specimens, in contrast with the natural infections of standard rodent hosts, and may be considered a likely pathological feature of H. nana infection in white-tailed antsangies. [ABSTRACT FROM AUTHOR]

Lymphoma is the most common tumour of domestic cats, developing most frequently in the small intestine. Feline small intestinal lymphoma predominantly demonstrates a T-cell immunophenotype identified by standard immunopositivity for T cells with CD3 or immunopositivity for B cells with CD20. In contrast, a wide spectrum of immunohistochemical antibodies are applied in humans to diagnose the various specific lymphoma subtypes according to the WHO classification. Our aim was to augment our knowledge of immunophenotypes in feline non-B-cell lymphomas forming macroscopic masses in the intestinal tract. We evaluated the combined immunohistochemistry and flow cytometry findings from 15 cases. Neoplastic lymphoid cells were immunopositive for CD3 in 93% (14/15), granzyme B in 87% (13/15), CD5 in 20% (3/15), CD8 in 13% (2/15), CD4 in 7% (1/15) and CD56 in 7% (1/15) of cases. Cytotoxic granules indicating a cytotoxic origin of the neoplastic cells were identified by histopathology only in 13% (2/15) and by cytology in 47% (7/15) of the cases. Without immunohistochemical labelling of the cytotoxic protein granzyme B, the cytotoxic status would have been missed in 46% (6/13) of the cytological and in 85% (11/13) of the histopathological slides. These findings suggest that more complex immunophenotyping may advance our understanding and help prognosticate small intestinal T-cell lymphoma in cats. [ABSTRACT FROM AUTHOR]

Information on the conditions under which drugs are transferred from the stomach through the upper small intestine after a high-calorie, high-fat meal is very limited. To simulate the drug presence after disintegration and arrival in the antral region, paracetamol solution and Sporanox® amorphous solid dispersion pellets at two dose levels were administered to the antrum of 8 healthy adults 30 min after administration of a high-calorie, high-fat meal on a crossover basis. The overall median buffer capacity of antral contents was estimated to be 18.0 and 24.0 mmol/ml/ΔpH when titrating with NaOH and HCl, respectively. The corresponding values for the contents of upper the small intestine were 14.0 and 16.8 mmol/ml/ΔpH, respectively. The drug transfer process from the antrum through the upper small intestine occurred with apparent first-order kinetics. The best estimate for the antral emptying half-life was 39min and 45min for paracetamol and itraconazole, respectively, the apparent volume of contents of the upper small intestine was more than double compared with previously reported values in the fasted state, the half-life of drug elimination from the upper small intestine was similar to recent estimates for highly permeable drugs in the fasted state, and the apparent volume of antral contents during the first couple of hours post drug administration was 303mL. Information collected in this study could increase the reliability of in silico and/or in vitro modelling approaches applied in clinical drug development. [Display omitted] [ABSTRACT FROM AUTHOR]

Crohn's disease is characterized by skip lesions with inflamed and adjacent non-inflamed mucosae in the small intestine and colon. Understanding the spatial organization of various regions within skip lesions can provide answers to their development and persistence. Alterations in the epithelium, lamina propria, and immune landscape have been noted in skip lesions. Host–microbiota interactions and intestinal barrier architecture are affected by inflammation, yet the measured changes are contradictory. Emerging techniques and technologies provide the foundation for uncovering spatial differences within skip lesions and applying the findings to improve candidate diagnostics, treatments, and identifying risk of recurrence. CD is characterized by enigmatic skip lesions, defined by discrete areas of inflammation demarcated from adjacent uninflamed regions. Their etiology and impact in CD might be solved by analyzing spatial analytic parameters in specific mucosal localities of inflamed and adjacent non-inflamed tissues, including microbial interactions, intestinal barrier, lamina propria, immune landscape, and mesenteric tissues. Recent technological advancements have increased our understanding of the spatial and functional changes within these lesions, including those involving host cells, mucus, and the microbiome, thus garnering a better understanding of mucosal tissue inflammation. Skip lesions are an enigmatic spatial feature characterizing Crohn's disease (CD). They comprise inflamed and adjacent non-inflamed tissue sections with a clear demarcation. Currently, spatial features of the human gastrointestinal (GI) system lack clarity regarding the organization of microbes, mucus, tissue, and host cells during inflammation. New technologies with multiplexing abilities and innovative approaches provide ways of examining the spatial organization of inflamed and non-inflamed tissues in CD, which may open new avenues for diagnosis, prognosis, and treatment. In this review, we present evidence of the relevance of spatial context in patients with CD and the methods and ideas recently published in studies of spatiality during inflammation. With this review, we aim to provide inspiration for further research to address existing gaps. [ABSTRACT FROM AUTHOR]

Postoperative prostate radiotherapy requires large planning target volume (PTV) margins to account for motion and deformation of the prostate bed. Adaptive radiation therapy (ART) can incorporate image-guidance data to personalize PTVs that maintain coverage while reducing toxicity. We present feasibility and dosimetry results of a prospective study of postprostatectomy ART. Twenty-one patients were treated with single-adaptation ART. Conventional treatments were delivered for fractions 1 to 6 and adapted plans for the remaining 27 fractions. Clinical target volumes (CTVs) and small bowel delineated on fraction 1 to 4 CBCT were used to generate adapted PTVs and planning organ-at-risk (OAR) volumes for adapted plans. PTV volume and OAR dose were compared between ART and conventional using Wilcoxon signed-rank tests. Weekly CBCT were used to assess the fraction of CTV covered by PTV, CTV D99, and small bowel D 1cc. Clinical metrics were compared using a Student's t-test (p < 0.05 significant). Offline adaptive planning required 1.9 ± 0.4 days (mean ± SD). ART decreased mean adapted PTV volume 61 ± 37 cc and bladder wall D50 compared with conventional treatment (p < 0.01). The CTV was fully covered for 96% (97%) of fractions with ART (conventional). Reconstructing dose on weekly CBCT, a nonsignificant reduction in CTV D99 was observed with ART (94%) compared to conventional (96%). Reduced CTV D99 with ART was significantly correlated with large anterior-posterior rectal diameter on simulation CT. ART reduced the number of fractions exceeding our institution's small bowel D1c limit from 14% to 7%. This study has demonstrated the feasibility of offline ART for post-prostatectomy cancer. ART facilitates PTV volume reduction while maintaining reasonable CTV coverage and can reduce the dose to adjacent normal tissues. [ABSTRACT FROM AUTHOR]

Omphalocele is an abnormality in which fetal abdominal organs protrude through the abdominal wall. We report the case of a 13-year-old female with a history of omphalocele repair who presented with acute periumbilical pain, nausea, and vomiting. A computed tomography scan showed a para-ovarian cyst and mild dilation of the small bowel. During laparoscopy, the right ovary and fallopian tube were detached from the uterus and located behind the cecum. Despite this displacement, the ovary appeared to have retained functionality with intact blood supply. We hypothesize that surgical repair led to pelvic adhesion that caused torsion and avulsion of the fallopian tube and utero-ovarian ligament that led to the displacement. This anatomical change should be considered in surgical patients with a history of omphalocele repair. [ABSTRACT FROM AUTHOR]

Revisional bariatric surgery (RBS) for insufficient weight loss/weight regain or metabolic relapse is increasing worldwide. There is currently no large multinational, prospective data on 30-day morbidity and mortality of RBS. In this study, we aimed to evaluate the 30-day morbidity and mortality of RBS at participating centres. An international steering group was formed to oversee the study. The steering group members invited bariatric surgeons worldwide to participate in this study. Ethical approval was obtained at the lead centre. Data were collected prospectively on all consecutive RBS patients operated between 15th May 2021 to 31st December 2021. Revisions for complications were excluded. A total of 65 global centres submitted data on 750 patients. Sleeve gastrectomy (n = 369, 49.2 %) was the most common primary surgery for which revision was performed. Revisional procedures performed included Roux-en-Y gastric bypass (RYGB) in 41.1 % (n = 308) patients, One anastomosis gastric bypass (OAGB) in 19.3 % (n = 145), Sleeve Gastrectomy (SG) in 16.7 % (n = 125) and other procedures in 22.9 % (n = 172) patients. Indications for revision included weight regain in 615(81.8 %) patients, inadequate weight loss in 127(16.9 %), inadequate diabetes control in 47(6.3 %) and diabetes relapse in 27(3.6 %). 30-day complications were seen in 80(10.7 %) patients. Forty-nine (6.5 %) complications were Clavien Dindo grade 3 or higher. Two patients (0.3 %) died within 30 days of RBS. RBS for insufficient weight loss/weight regain or metabolic relapse is associated with 10.7 % morbidity and 0.3 % mortality. Sleeve gastrectomy is the most common primary procedure to undergo revisional bariatric surgery, while Roux-en-Y gastric bypass is the most commonly performed revision. [ABSTRACT FROM AUTHOR]

Scrotal hernia is an inguinal hernia, in which the visceral organs protrude through the inguinal ring into the scrotum. No clinical report of a scrotal hernia in a ferret has been documented based on the literature search. A one-year-old intact male ferret was presented with a history of several months of slowly progressive, right, cord-like scrotal swelling. On physical examination, a scrotal hernia was suspected and the protruding contents were unable to be reduced. Radiography and ultrasonography revealed a herniated small intestinal loop inside the swollen scrotum which confirmed the diagnosis of irreducible scrotal hernia. Following reduction of the small intestine into the abdomen, inguinal herniorrhaphy and castration were performed. Recurrence and other clinical abnormalities were not identified during post-operative follow-ups at 3 months and 1 year. This case involved a scrotal hernia in an intact male ferret with an irreducible herniated small intestine. This report describes the diagnostic findings and surgical treatment with a successful outcome. Scrotal hernia should be considered in ferrets with scrotal swelling. [ABSTRACT FROM AUTHOR]

To evaluate simulated parastomal herniation forces in in vitro abdominal fascial models. Our group previously illustrated how incision type may play a consequential role in bowel herniation force generated across an incision using several abdominal fascia models. We sought to (1) Confirm findings in fresh human tissue, (2) Assess correlation between herniation force and incision size, and (3) Determine whether incision type impacts drainage in a simulated ex vivo ileal conduit. Axial tension force (N) of herniation was measured using our previously published protocol, pulling a Foley catheter balloon 3.8 cm diameter affixed to a dynamometer through silicone/fascial incisions ranging 3-5.8 cm. We simulated ileal conduits using bovine small intestine with stoma matured through human fascia using 3.0 cm linear or cruciate incisions. The conduit's caudal end was catheterized and filled at 20 mL/min. Drainage was measured by pad weight change. Two-sided α < 0.05 was used to reject the null hypothesis. Mean (±SD) herniation forces in fresh human fascia varied significantly across linear longitudinal, linear transverse, and cruciate incisions (20.9 ± 3.7, 23.3 ± 8.8, and 8.9 ± 3.8 N, respectively [ P =.011]). Fresh human fascial linear incisions 3 cm in diameter had a herniation force of 22.1 ± 6.3 vs 3.5 ± 0.7 N for 5.8 cm incisions when herniating a 3.8 cm balloon (P =.002). All observations were similar in silicone. In simulated ileal conduit, mean drainage: 70.8 ± 3.6 vs 82.1 ± 9.7 mL (linear vs cruciate) after 100 mL instilled, respectively (P =.05). This ex vivo study further suggests incision type has predictable influence on herniation force. These data support standardization of urostomy construction techniques and evaluating the clinical impact of stomal maturation techniques on parastomal hernia rates. [ABSTRACT FROM AUTHOR]

This study surveyed radiation oncologists in Morocco to explore current practices and perspectives on brachytherapy for cervix cancer. A 37-question survey was conducted in April 2023 among 165 Moroccan radiation oncologists using Google Forms. Of the 93 respondents, 39% treated over 20 patients in 2022 using 3D image-guided brachytherapy (BT) through the HDR technique; 2D techniques were not reported in the last five years. Intracavitary BT is uniformly applied with a tandem and ovoid applicator. Only 14% utilized interstitial needles for hybrid BT. Iridium-192 was the primary radioactive source (63%), followed by cobalt (37%). Ultrasound-guided 47% of applicator insertions. All used CT scans for planning, but only 6% used MRI fusion due to limited availability. Guidelines for target volume and dose prescription were mostly based on GEC-ESTRO recommendations (74%), followed by Manchester Point A (30.4%) and ABS (11%). Over 90% delineated CTV-HR and CTV-IR; 30% delineated GTV. All marked the bladder and rectum, while 52% marked the sigmoid, 5% the small bowel, and 3% the recto-vaginal point. For dosimetry, 12% used ICRU 89 points, 54% used dose-volume histograms (DVH), and 36% used both. Most reported EQD2cc for OARs for the rectum and bladder, with nine still using ICRU point doses. The most common fractionation schema was 7 Gy in four fractions (60%) and 7 Gy in three fractions (55%). Brachytherapy remains essential for treating cervical cancer in Morocco. Key areas for improvement include MRI fusion-guided brachytherapy, access to advanced applicators, expanding interstitial techniques, and professional training and national referential. [ABSTRACT FROM AUTHOR]

Food allergen sensitization is characterized by a type 2 immune response towards a specific food protein and can adversely affect the patient after re-exposure of this food allergen. The gut, skin, and lymph nodes (including immune cells) are interconnected key organs in food allergen sensitization. Gut and skin organ-on-a-chip (OoC) devices have been developed with an immune component to recapitulate the 3D epithelial cell–immune cell crosstalk, although specialized gut–immune–skin OoC models to study food protein sensitizing allergenicity capacity are not available yet. The inclusion of compartmentalized innate and adaptive immune cells is crucial to mimic the immune cascade in the gut–immune–skin axis in a stepwise manner. Engineering a gut–immune–skin axis OoC can better evaluate food allergen sensitization in the future and advance mechanistic insight. The global population is growing, rapidly increasing the demand for sustainable, novel, and safe food proteins with minimal risks of food allergy. In vitro testing of allergy-sensitizing capacity is predominantly based on 2D assays. However, these lack the 3D environment and crosstalk between the gut, skin, and immune cells essential for allergy prediction. Organ-on-a-chip (OoC) technologies are promising to study type 2 immune activation required for sensitization, initiated in the small intestine or skin, in interlinked systems. Increasing the mechanistic understanding and, moreover, finding new strategies to study interorgan communication is of importance to recapitulate food allergen sensitization in vitro. Here, we outline recently developed OoC platforms and discuss the features needed for reliable prediction of sensitizing allergenicity of proteins. [ABSTRACT FROM AUTHOR]

The kampong chicken farming industry has excellent potential to develop in Indonesia. Therefore, it is necessary to understand the growth of kampong chickens in order to obtain an optimal quality of meat and eggs. This research aims to study the growth morphology of the gastrointestinal tract, pectoralis thoracicus muscle, lymphoid organs and visceral index in kampong chickens. In this study, 100 male and female KUB (Kampung Unggul Balitbangtan) chickens were used, which were reared from post-hatching to 63 days of age. Parameters measured were body weight, organ index, body morphometry, and morphology of small intestine, pectoralis thoracicus muscle, and lymphoid organs. Organ histological preparations were made using paraffin methods, Hematoxylin-Eosin (HE), and Periodic Acid Schiff-Alcian Blue (PAS-AB) staining. The results showed that the growth rate of the small intestine and the lymphoid organ peaked at 35 to 49 days of age, while the maximal growth rate of the pectoralis thoracicus muscle occurred at 21 to 35 days and experienced a decrease later at 35 days. The growth index of the viscera started to decrease at 35 days. Body weight reached optimum growth rate at 42 to 45 days of age, while chicken body morphometry continued to increase until 63 days old. The conclusions of the study is that the small intestine, pectoralis thoracicus muscle, and lymphoid organ of kampong chicken experienced rapid growth during 35 to 49 days post-hatch. Therefore, in kampong chicken, the appropriate nutritional management should be increased between day zero and 49 post-hatch. [ABSTRACT FROM AUTHOR]

Tissue uptake and distribution of nano-/microplastics was studied at a single high dose by gavage in vivo. Fluorescent microspheres (100 nm, 3 μm, and 10 μm) were given once at a dose of 200 mg/(kg·body weight). The fluorescence intensity (FI) in observed organs was measured using the IVIS Spectrum at 0.5, 1, 2, and 4 h after administration. Histopathology was performed to corroborate these findings. In the 100 nm group, the FI of the stomach and small intestine were highest at 0.5 h, and the FI of the large intestine, excrement, lung, kidney, liver, and skeletal muscles were highest at 4 h compared with the control group (P < 0.05). In the 3 μm group, the FI only increased in the lung at 2 h (P < 0.05). In the 10 μm group, the FI increased in the large intestine and excrement at 2 h, and in the kidney at 4 h (P < 0.05). The presence of nano-/microplastics in tissues was further verified by histopathology. The peak time of nanoplastic absorption in blood was confirmed. Nanoplastics translocated rapidly to observed organs/tissues through blood circulation; however, only small amounts of MPs could penetrate the organs. [ABSTRACT FROM AUTHOR]

While a number of enteric coatings and pH-sensitive oral delivery vehicles have been developed, they lack the ability to sufficiently protect proteins from proteolytic degradation once released from the carrier. In this work, we show that H-bonded, pH-sensitive poly(methacrylic acid-grafted ethylene glycol) glycol (henceforth designated as P(MAA-g-EG) gels) exhibit great promise as protein carriers, as they utilize poly(ethylene glycol) (PEG) chains to promote mucoadhesion in the small intestine, increasing the chances that the drug is released within the villus of the absorptive intestinal wall. Importantly, PEG was also conjugated to the B29-lysine (LysB29) position of insulin in order to protect the drug from proteolytic degradation once released in the small intestine and adhere the drug to the intestinal epithelium through improved mucoadhesion. PEG-conjugated (PEGylated) molecules were found to actively participate in the carrier loading and release mechanism, with the drug conjugate hydrogen bonding to the MAA while in the collapsed state and subsequently repulse the drug above the polymer's isoelectric point. This effect was enhanced through the evaluation of PEG graft density within the carrier. Cellular transport and changes in transepithelial resistance caused by the PEGylated insulin (PI) in the presence of P(MAA-g-EG) microparticles were analyzed using a 1:1 co-culture of human colon adenocarcinoma (Caco-2) and: the mucus-secreting human colon carcinoma cell(HT-29-MTX). Finally, the in vivo absorption of insulin was measured in Sprague-Dawley rats to ensure that the PEGylated insulin conjugates are biologically active, as well as to compare the bioavailability to control insulin. Collectively, these results lead toward the development of a novel system for improved insulin delivery, with improved stability of insulin through PEGylation. [Display omitted] [ABSTRACT FROM AUTHOR]

Adhesion G protein-coupled receptors (aGPCRs) feature large extracellular regions with modular domains that often resemble protein classes of various function. The pentraxin (PTX) domain, which is predicted by sequence homology within the extracellular region of four different aGPCR members, is well known to form pentamers and other oligomers. Oligomerization of GPCRs is frequently reported and mainly driven by interactions of the seven-transmembrane region and N or C termini. While the functional importance of dimers is well-established for some class C GPCRs, relatively little is known about aGPCR multimerization. Here, we showcase the example of ADGRG4, an orphan aGPCR that possesses a PTX-like domain at its very N-terminal tip, followed by an extremely long stalk containing serine-threonine repeats. Using X-ray crystallography and biophysical methods, we determined the structure of this unusual PTX-like domain and provide experimental evidence for a homodimer equilibrium of this domain which is Ca2+-independent and driven by intermolecular contacts that differ vastly from the known soluble PTXs. The formation of this dimer seems to be conserved in mammalian ADGRG4 indicating functional relevance. Our data alongside of theoretical considerations lead to the hypothesis that ADGRG4 acts as an in vivo sensor for shear forces in enterochromaffin and Paneth cells of the small intestine. [ABSTRACT FROM AUTHOR]

Our purpose was to develop a deep learning model (AbsegNet) that produces accurate contours of 16 organs at risk (OARs) for abdominal malignancies as an essential part of fully automated radiation treatment planning. Three data sets with 544 computed tomography scans were retrospectively collected. Data set 1 was split into 300 training cases and 128 test cases (cohort 1) for AbsegNet. Data set 2, including cohort 2 (n = 24) and cohort 3 (n = 20), were used to validate AbsegNet externally. Data set 3, including cohort 4 (n = 40) and cohort 5 (n = 32), were used to clinically assess the accuracy of AbsegNet-generated contours. Each cohort was from a different center. The Dice similarity coefficient and 95th-percentile Hausdorff distance were calculated to evaluate the delineation quality for each OAR. Clinical accuracy evaluation was classified into 4 levels: no revision, minor revisions (0% < volumetric revision degrees [VRD] ≤ 10%), moderate revisions (10% ≤ VRD < 20%), and major revisions (VRD ≥20%). For all OARs, AbsegNet achieved a mean Dice similarity coefficient of 86.73%, 85.65%, and 88.04% in cohorts 1, 2, and 3, respectively, and a mean 95th-percentile Hausdorff distance of 8.92, 10.18, and 12.40 mm, respectively. The performance of AbsegNet outperformed SwinUNETR, DeepLabV3+, Attention-UNet, UNet, and 3D-UNet. When experts evaluated contours from cohorts 4 and 5, 4 OARs (liver, kidney_L, kidney_R, and spleen) of all patients were scored as having no revision, and over 87.5% of patients with contours of the stomach, esophagus, adrenals, or rectum were considered as having no or minor revisions. Only 15.0% of patients with colon and small bowel contours required major revisions. We propose a novel deep-learning model to delineate OARs on diverse data sets. Most contours produced by AbsegNet are accurate and robust and are, therefore, clinically applicable and helpful to facilitate radiation therapy workflow. [ABSTRACT FROM AUTHOR]

The present study aims to describe the intestine and pancreas of both Dryadonycteris capixaba and Pygoderma bilabiatum. Furthermore, it aims to identify the enteroendocrine cells that produce serotonin (5-HT), somatostatin (SST), and cholecystokinin (CCK) in the intestine and CCK, SST, glucagon (CGC) and insulin (INS) in the pancreas, relating histological characteristics with feeding habits, besides contributing to basic research on aspects of the diffuse neuroendocrine system of mammals. Histologically, the intestinal wall of the species D. capixaba and P. bilabiatum was similar to that of other mammals. The height of the villi in the small intestine was different among the species studied. In the duodenum and ileum, PAS positive secretion was observed. The duodenal gland present only in P. bilabiatum showed intense reaction for PAS stain, indicating neutral glycosaminoglycans (GAGs). The frequency and distribution of 5-HT Immunoreactive (IR) cells varied among the species. In D. capixaba , these cells were evident only in the ileum (11.8 ± 2.9 μm) and large intestine region. In P. bilabiatum were different among the segments, with the highest frequency in the duodenum (13.3 ± 2.8 μm), jejunum (8.1 ± 2.3 μm) and ileum (10.1 ± 1.9 μm). CCK-IR cells were not observed in D. capixaba. In P. bilabiatum these cells were observed in the ileum (9.5 ± 1.3 μm). SST-IR cells were not found throughout the intestine of the studied species. The pancreas of bats presents islets with differentiated cellular composition. All the antibodies used (CCK, SST, GCG and INS) obtained positive staining in the pancreatic islets of both the species studied. The INS-IR cells marked the entire islet in both species, whereas the CGC-IR cells were visualized throughout the islet in D. capixaba and preferentially in the periphery in P. bilabiatum. CCK and SST-IR cells were located in the peripheral region of the islets in both species. In our study we observed similarities in the intestinal and pancreatic morphology of the studied species, although there were interspecific differences in the distribution of intestinal GAGs and enteroendocrine cells. This suggests that these differences may be more related to the distinct feeding habits of each species than to their phylogeny, as they belong to the same family. [ABSTRACT FROM AUTHOR]

Background: SBO is a potentially life-threatening condition that often affects older patients. Frailty, more than age, is expected to play a crucial role in predicting SBO prognosis in this population. This study aims to define the influence of Clinical Frailty Scale (CFS) on mortality and major complications in patients ≥80 years with diagnosis of SBO at the emergency department (ED). Methods: All patients aged ≥80 years admitted to our ED for SBO from January 2015 to September 2020 were enrolled. Frailty was assessed through the CFS, and then analyzed both as a continuous and a dichotomous variable. The endpoints were in-hospital mortality and major complications. Results: A total of 424 patients were enrolled. Higher mortality (20.8% vs 8.6%, p<0.001), longer hospital stay (9 [range 5–14] days vs 7 [range 4–12] days, p=0.014), and higher rate of major complications (29.9% vs 17.9%, p=0.004) were associated with CFS ≥7. CFS score and bloodstream infection were the only independent prognostic factors for mortality (OR 1.72 [CI: 1.29–2.29], p<0.001; OR 4.69 [CI: 1.74–12.6], p=0.002, respectively). Furthermore, CFS score, male sex and surgery were predictive factors for major complications (OR 1.41 [CI: 1.13–1.75], p=0.002; OR 1.67 [CI: 1.03–2.71], p=0.038); OR 1.91 [CI: 1.17–3.12], p=0.01; respectively). At multivariate analysis, for every 1-point increase in CFS score, the odds of mortality and the odds of major complications increased 1.72-fold and 1.41-fold, respectively. Conclusion: The increase in CFS is directly associated with an increased risk of mortality and major complications. The presence of severe frailty could effectively predict an increased risk of in-hospital death regardless of the treatment administered. The employment of CFS in elderly patients could help the identification of the need for closer monitoring and proper goals of care. [ABSTRACT FROM AUTHOR]

Methods All the clinical records of consecutive patients >= 65 years admitted to our ED from January 1, 2014, to December 31, 2021, were evaluated, and all patients with a diagnosis of ASBO were recruited and assigned to the NOM or surgical group. Keywords: Small Bowel Obstruction (SBO); Elderly; NOM; Morbidity; Mortality EN Small Bowel Obstruction (SBO) Elderly NOM Morbidity Mortality 2218 2222 5 10/18/23 20231001 NES 231001 Fausto Rosa and Marcello Covino contributed equally to this work. [Extracted from the article]

This review highlights the importance of controlling the digestion process of orally administered lipid-based delivery systems (LBDS) and their performance. Oral LBDS are prone to digestion via pancreatic lipase in the small intestine. Rapid or uncontrolled digestion may cause the loss of delivery system integrity, its structural changes, reduced solubilization capacity and physical stability issues. All these events can lead to uncontrolled drug release from the digested LBDS into the gastrointestinal environment, exposing the incorporated drug to precipitation or degradation by luminal proteases. To prevent this, the digestion rate of orally administered LBDS can be estimated by appropriate choice of the formulation type, excipient combinations and their ratios. In addition, in vitro digestion models like pH-stat are useful tools to evaluate the formulation digestion rate. Controlling digestion can be achieved by conventional lipase inhibitors like orlistat, sterically hindering of lipase adsorption on the delivery system surface with polyethylene glycol (PEG) chains, lipase desorption or saturation of the interface with surfactants as well as formulating LBDS with ester-free excipients. Recent in vivo studies demonstrated that digestion inhibition lead to altered pharmacokinetic profiles, where C max and T max were reduced in spite of same AUC compared to control or even improved oral bioavailability. [Display omitted] [ABSTRACT FROM AUTHOR]

• Managing COVID-19 infection in transplant patients receiving immunosuppressive therapy requires special consideration in selecting anti-COVID-19 drugs. • Potential side effects of anti-COVID-19 drugs and possible interactions between immunosuppressants and anti-COVID-19 drugs should be well understood. The COVID-19 pandemic has caused millions of people to become infected worldwide. Some patients may have disease progression and may need treatment with an anti–COVID-19 agent, hospitalization, and even intensive care. The risk factors for disease progression include old age, diabetes mellitus, pulmonary disease, cardiac disease, immunodeficiency, and immunosuppressant treatment. Therefore, managing COVID-19 infection in transplant patients under immunosuppressant treatments needs specific consideration, especially the side effects of anti–COVID-19 agents and the interaction between immunosuppressants and anti–COVID-19 agents. In this report, we present the case of a small bowel transplant patient who had a COVID-19 infection. The patient was initially treated for paxlovid, and she developed bloody stools and dizziness. The treatment was then changed to molnupiravir without discontinuation of tacrolimus. The patient recovered smoothly after a 5-day treatment with molnupiravir. Here, we discuss the management experience of such patients and review the relevant literature. [ABSTRACT FROM AUTHOR]

The greater omentum is a unique anatomical structure that serves a critical function in the containment of inflammatory and infectious processes within the abdominal cavity. It is also a common site of involvement by metastases, as well as the primary location for various pathologic lesions of clinical significance. Its fibroadipose composition, large size, and position in the most anterior aspect of abdomen allow accurate visualization of the greater omentum on CT and MR images. Careful evaluation of the greater omentum can provide important clues to the diagnosis of the underlying abdominal disorder. The aim of this article is to present the normal appearance of the greater omentum, and the wide spectrum of its pathological features as demonstrated on CT and MRI of the abdomen. • The greater omentum is a fibroadipose apron attached to the stomach and transverse colon. • It is the most anterior component of peritoneal cavity and covers the small bowel loops. • It represents a common site of involvement by inflammatory and neoplastic processes. • Its normal and pathological features can be easily evaluated on CT and MR images. • These findings are important for the diagnosis and management of abdominal disorders. [ABSTRACT FROM AUTHOR]

The objective of this work was to evaluate dosimetric characteristics to organs at risk (OARs) from short-course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared with standard of care (SOC) in a multi-institutional prospective randomized trial. SAVE (Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care) is a prospective, phase 3, multisite randomized trial in which 108 patients requiring VCB were randomized to an experimental short-course arm (11 Gy × 2 fractions [fx] to surface) and SOC arm. Those randomized to the SOC arm were subdivided into treatment groups based on treating physician discretion as follows: 7 Gy × 3 fx to 5 mm, 5 to 5.5 Gy × 4 fx to 5 mm, and 6 Gy × 5 fx to surface. To evaluate doses to OARs of each SAVE cohort, the rectum, bladder, sigmoid, small bowel, and urethra were contoured on planning computed tomography, and doses to OARs were compared by treatment arm. Absolute doses for each OAR and from each fractionation scheme were converted to 2 Gy equivalent dose (EQD2 3). Each SOC arm was compared with the experimental arm separately using 1-way analysis of variance, followed by pairwise comparisons using Tukey's honestly significant difference test. The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra compared with the 7 Gy × 3 and 5 to 5.5 Gy × 4 fractionation schemes; however, the experimental arm did not differ from the 6 Gy × 5 fractionation scheme. For small bowel doses, none of the SOC fractionation schemes were statistically different than the experimental. The highest EQD2 3 doses to the examined OARs were observed to come from the most common dose fractionation scheme of 7 Gy × 3 fx. With a short median follow-up of 1 year, there have been no isolated vaginal recurrences. Experimental short-course VCB of 11 Gy × 2 fx to the surface provides a comparable biologically effective dose to SOC courses. Experimental short-course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD2 3 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late adverse effects. [ABSTRACT FROM AUTHOR]

Resection of neuroendocrine tumors (NET) with surgical debulking of liver metastasis (NETLM) is associated with improved survival. In patients with an unknown primary (UP-NETLM), the effects of debulking remains unclear. The National Cancer Database (2004–2016) was queried for patients with small intestine (SI) and pancreas (P) NETLMs. If the liver was listed as the primary site, the patient's disease was classified as UP-NETLM. Patients with UP-NETLM, SI-NETLM, and P-NETLM who were managed non-operatively demonstrated a significant difference in 5-year overall survival (OS) (21.5% vs. 39.2% vs. 17.1%; p < 0.0001). OS in patients who underwent debulking was higher (63.7% vs. 73.2% vs. 54.2%). Patients with UP-NETLMs who underwent debulking had similar OS to patient with SI-NETLM (p = 0.051), but significantly higher OS, depending on tumor differentiation, compared to patients with P-NETLMs. If well-differentiated, surgery for UP-NETLMs was associated with a higher rate of OS (p = 0.009), while no difference was observed if moderately (p = 0.209) or poorly/undifferentiated (p = 0.633). P-NETLMs were associated with worse OS (p < 0.001) on multivariate analysis. Debulking in patients with UP-NETLMs was associated with similar OS compared to patients with SI-NETLMs and better or similar OS compared to patient with P-NETLMs. [ABSTRACT FROM AUTHOR]

The EMBRACE II study (2018) came with recommendations to de-escalate vaginal dose during the treatment of cervical cancers using tandem and ovoid applicators. Historically, organs at risk included bladder, rectum, sigmoid, and small bowel. The inclusion of vaginal dose has become widely discussed in recent years to limit side effects including vaginal stenosis to promote sexual function and quality of life. The EMRACE II study identified ways to reduce such side effects, including limiting the ICRU recto-vaginal point dose to 65 Gy and 45 Gy (EBRT), in addition to reduction of source loading in the rings or ovoids without compromising high risk control tumor volume (HR-CTV) coverage. In this study, we retrospectively evaluated vaginal dose, and ovoid loading in a group of patients treated with EBRT and HDR for cervical cancer. A cohort of 35 patients recently treated with a tandem and ovoid applicator were evaluated. After 45 Gy of EBRT, HDR brachytherapy was used to provide a total EQD2 HR-CTV dose of >85 Gy. The HR-CTV was delineated on the first fraction with MRI. Vaginal dose was retrospectively evaluated at the surface of the left and right ovoid for each fraction. The point dose was defined as the most lateral point of the ovoid channel, on the surface of the applicator. To determine dose de-escalation potential, patients were divided into two categories: HR-CTV touching the ovoids, and those without (patients with superior tumors). Of the 35 patients studied, 21 (60%) had an HR-CTV not touching the ovoids, and 14 (40%) had an HR-CTV extending inferiorly to the ovoid surface. Of the patients with HR-CTV touching the ovoids, 7 cases (50%) featured an unnecessary extension of the 140% isodose line into the vaginal wall. Of patients with superior HR-CTVs (not touching the ovoid's), only 3 (14%) had an unnecessary extension the 140% isodose line extending outside the applicator into the vaginal wall. Through the analysis, variability of ovoid loading between fractions was evident despite similar HR-CTV contours. In one case for example, ovoid loading varied between from 29% to 157% (see figure). The HR-CTV coverage had a V100% of 90.3, 88.2, 94.1, and 93.6% for fractions number 1-4. In this example, it is evident that fraction number 2 had more ovoid loading than necessary for HR-CTV coverage. The EMBRACE II recommendations provide evidence that vaginal dose de-escalation is feasible, and can help improve the quality of life and sexual function for women post-treatment for cervical cancer. We observed inter-fractional differences in vaginal dose, for cases with and without the HR-CTV touching the ovoids. In our retrospective review, several cases had unnecessary dose to the vagina that could be limited, highlighting the importance of implementing updated and uniform dose goals. This review has shown the possibility of improving the quality of care by systematically analyzing previous treatment plans and providing plan quality feedback to the brachytherapy team based on ovoid doses. Such feedback can also improve continuity across physicists and physician teams to minimize variability across treatment plans. By integrating this feedback into clinical practice, we aim to further refine treatment planning strategies and ensure the delivery of optimal care to the patients. [ABSTRACT FROM AUTHOR]

Artificial Intelligence (AI)-based prediction models have increasing applications for automation in brachytherapy (BT) with promise to improve workflow efficiency and treatment accuracy. Manual segmentation is an area that has benefitted immensely from AI assistance. However, even well-structured AI models for contouring can harbor inconsistencies making them unsuitable for clinician-specific application. Deep learning (DL)-based autosegmentation has not been explored for personalized use in BT. We aim to assess properties of model architectures customized for individual contouring practice. 200 T2-weighted 3D MRI scans taken at time of intracavitary ± interstitial (IS) BT for locally advanced cervix cancer (03/2016 - 01/2024) were prepared for DL-model development (Pooled Model; PoM). All featured 4 organs-at-risk (OARs; bladder (BLD), rectum (REC), sigmoid (SIG), small bowel (SB)) contoured on 1 mm slices (Ground Truth; GT) by 3 experienced radiation oncologists (RO; % cases 35:34:31) per EMBRACE 2 definitions. Clinically used images included tandem and multiple vaginal components (IS ring, Utrecht, Venezia, Geneva, multichannel cylinder; Elekta, Sweden). Personalized models (PeM1-3; 60 cases each) were built for each RO using their own contours, then tested for inter-RO applicability and against PoM for variability. PoM and PeM models were compared using several metrics; Dice Coefficient (DC) and Hausdorff Distance (HD) reported here. Contours were qualitatively evaluated by the ROs using a 5-point Likert scale (1 accept for clinical use, 2 minor changes, 3 major changes, 4 reject, 5 undecided). Following a thorough investigation of several AI-models, nnUNet architecture-based PoM and PeMs were generated using 5-fold cross validation for training (batch size 2, patch size 160 × 128 × 112, epochs 500, Dice and cross-entropy loss function, LeakyReLU activation function, momentum optimizer, initial learning rate 0.01, max data size 512 × 512 × 250). Both PoM and PeM datasets were separated for training (70%), validation (15%), and testing (15%). Compared to GT, PoM-predicted contours yielded median[min - max] DC and HD (mm) for BLD of 0.93[0.85-0.97] and 7.2[4.1-35.3], REC 0.88[0.49-0.93] and 11.5[4.1-55.3], SIG 0.77[0.30-0.92] and 30.6[5.3-91.2], and SB 0.61[0.14-0.89] and 42.9[19.1-89.9]. Across all PeMs and the PoM, higher consistency was seen for OARs with less variable GT volumes (Figs A and B; BLD vs SB). Regardless of which RO's contours were used to train individual models, PeM metrics were similar, with BLD (Fig A; DC>0.92) and REC contours produced to a high degree of fidelity. There could be unknown factors relating to patient anatomy, but also baseline similarities in contouring routines between ROs. One PeM outperformed (but p>0.05) PoM metrics when examined on its own testing set for all OARs and the PoM's testing set for OARs with high volume variability (SIG and SB; Figs A-D, PoMwithPeM2). The ROs ranked DL-contours as 1 or 2 (86%; rest as 3) on the Likert scale. Model fitting to anatomy distorted by various applicator configurations did not differ qualitatively from GT (Fig E). With sufficient data, PeM algorithms can be trained in a similar timeframe as POM (<105 hrs) to produce results most relevant for personalized RO use. Autosegmentation that mimics personal practice is feasible to build from real-world cervix MR BT applicator scenarios. Despite training on separate personalized datasets, a DL-model generated to represent one RO's contouring practice can produce contours closer to another RO's contouring approach without added training. Continuous retraining can improve personalized DL-autosegmentation algorithms. [ABSTRACT FROM AUTHOR]

Vaginal cuff brachytherapy (VCB) is recommended as integral adjuvant radiotherapy for early-stage postoperative endometrial cancer with high-intermediate risk. The time-consuming delineation emphasizes the urgent need for automatic segmentation of organs at risk (OARs) in computed tomography (CT)-guided VCB to improve consistency and efficiency. However general deep-learning (DL) methods were hampered by the limited high-quality medical image samples. This study amied to develop a DL model that introduced the "prompt" in Segment anything model (SAM) network to achieve accurate segmentation in limited training samples and comprehensively evaluated its accuracy and clinical feasibility. CT images of 126 postoperative EC patients who received VCB were enrolled and randomly divided into 100 for training and 26 for testing. Five OARs including rectum, colon, small intestine, bladder, and urethra were manually contoured by radiation oncologists. We proposed the 3D Prompt Res-nnUnet framework, a DL model enhanced by the two-part prompt-based section into the Res-nnUnet. For geometric evaluation, Dice similarity coefficient (DSC), Intersection over union (IoU), Hausdorff distance (HD), 95% Hausdorff distance (HD95), and Mean surface distance (MSD) were used. The dosimetric evaluation was conducted by comparing the dose-volume index (DVI) of manual and two DL-based segmentations generated on three different plans: original plans optimized for the manual segmentation (Plan_M), new plans with the same dwell time (Plan_S), and new plans reoptimized for the Prompt Res-nnUnet segmentation (Plan_P). Plan_P aimed to evaluate the clinical feasibility by applying automatically delineated structures directly to the clinical workflow using Bland-Altman analysis. Oncologist qualitative evaluation was performed by two experienced clinical oncologists using a 4-point scale. Prompt Res-nnUnet achieved high geometric accuracy with the mean DSC 0.900 for rectum, 0.848 for colon, 0.879 for small intestine, 0.953 for bladder, and 0.829 for urethra, all better than those of baseline Res-nnUnet. The HD95 were 3.796, 9.272, 11.907, 3.074, and 1.603 for rectum, colon, small intestine, bladder, and urethra, respectively. In dosimetric evaluation, the DVI of rectal and urethra based on Plan_M and Plan_S had statistical differences among the three delineations (all p < 0.001). Res-nnUnet delineation was statistically different from manual or Prompt Res-nnUnet delineation in pairwise comparisons. For clinical feasibility assessment based on Plan_P, Bland-Altman plots displayed good agreement between DVI of manual and Prompt Res-nnUnet with ≥24/26 (92.3%) points within 95% limits of agreement. Oncologist qualitative evaluation showed more than 65% segmentations of two DL-based methods were Point 1 or 2 (requires no or small modification), and Prompt Res-nnUnet outperformed Res-nnUnet for rectum, small intestine, bladder, and urethra (all p < 0.05). The proposed Prompt Res-nnUnet obtained superior performance than Res-nnUnet and high consistency with manual delineation. The results also demonstrate the feasibility of applying Prompt Res-nnUnet predicted delineation into clinical workflow. [ABSTRACT FROM AUTHOR]

The adoption of IGABT is limited in LMIC. This could be from lack of training in contouring, evaluation of volumetric plan and access to MRI. In most of the centres CT scan was routinely done for at least one fraction with applicator in situ but dose to target and OAR was still reported and optimized to points. MRI was seldom done at any point during course of radiation and brachytherapy schedule was 3-4 fractions performed weekly prolonging total treatment duration to be more than 55 days. Live and virtual workshop was performed over 1.5 days for hands on training with both physicians and physicists from all sites in December 2022. Workshop focused on use of sonogram for placement of applicator, CT scan-based contouring and planning with volumetric dose constraints, 3D MRI with T2 sequence whenever feasible, and use of hybrid applicator when available. First day was discussion on guidelines, contouring and data followed by hands on contouring of 3 cases on CT scan by all physicians. On second day entire workflow was demonstrated with live case with use of ultrasound, placement of hybrid applicator, contouring on CT scan and MRI and planning with clinical goals. Later most of the physicians were asked to perform IGBT procedure in the presence of an expert or a fellow physician practicing IGBT at their centre in this network. All participants were asked to share anonymized data for analyses of practice pattern after the workshop. The data was collected after 13 months from the initial workshop. Eleven out of 15 physicians from 6 sites agreed to share their dosimetry and early outcome data. All 11 physicians transitioned from point A to volume-based planning and treated 257 consecutive patients with IGBT (CT based 85% and MRI based 15%). 76% had MRI pelvis done before brachytherapy as part of workup. The commonest EBRT dose schedule was 45 in 25 fraction (60%) and HDR schedule was 21-28 Gy in 3-4 fraction (95%). For those who had EBRT in the network 97.2% received EBRT dose of 45 Gy in 25 fractions and HDR Schedule of 28 Gy in 4 fractions. Majority had intracavitary alone (86%) while 14% used hybrid applicator. Median D90 for HRCTV and D2cc for rectum, bladder, sigmoid and small bowel were 80.8Gy (79.28-85.05 Gy), 62.18Gy (57.5-66.8Gy), 63.87Gy (582-72Gy), 61.2 Gy (55.5-68.6Gy) and 55.1 Gy (45-63.6Gy) respectively. Overall treatment time was ≤ 50 days and ≤55 days for 64.9 % and 78.9% respectively for all patients and 72.2% and 88.9% for patients who received EBRT plus brachy at same location. The first follow up between 3-6 months was available for 148 patients and 138 (93.9%) had clinical and/or metabolic complete response. This workshop model of Identifying baseline practice pattern with education and training focused on specific quality aspect of RT delivery showed significant changes with adoption of IGBT, use of MRI and reduction of overall treatment time. The transition from point based to CT/MRI based IGBT was with high adherence to clinical goals and excellent early response. [ABSTRACT FROM AUTHOR]

We present a preliminary CT-guided online adaptive radiation therapy (CT-ART) experience in stereotactic body radiation therapy (SBRT) for liver tumors. Patients with hepatocellular carcinoma or liver metastasis treated with CT-ART were enrolled on a retrospective registry study. Physicians were offered 2 plans, the original plan transposed on a CBCT with adapted contours (sched) and a new plan generated with updated contours (adap). Student's t-test compared pt time in vault (TIV), planning target volume (PTV) coverage, and organs at risk (OAR) dose. χ2 test compared dose constraint violations. Thirteen pt (median age: 67, median ECOG: 1, 85% male) received SBRT 45 – 60 Gy (median: 50 Gy) in 5 fractions (fx). Median PTV 98.6 cc (range: 15.5 - 590.4 cc). Of 65 fx, 77% (50) were adapted. PTV V100%≥95% criteria were not met in 35% of scheduled and 6% of adapted plans (p < 0.001). Mean PTV V100% was not significantly different among all plans (sched: 94.9%, adap: 95.7%; p = 0.088). Mean internal target volume (ITV) D100% was better for all adapted plans (sched: 8.89Gy/fx, adap: 9.31Gy/fx; p = 0.003). Mean PTV V100% coverage was better for adapted plans when PTV and OAR overlapped (sched: 93.2%, adap: 95.1%; p = 0.046). Nearest OAR maximum point dose (Dmax) was lower for adapted plans when PTV-OAR overlapped (p = 0.025). Mean stomach Dmax was lower for adapted plans (sched: 4.1 Gy/fx, adap: 3.3 Gy/fx; p = 0.001), with 5 scheduled plans not meeting criteria. Mean small bowel Dmax was lower for adapted plans (sched: 3.2Gy/fx, adap: 2.6 Gy/fx; p = 0.006), with 2 scheduled plans not meeting criteria. Mean heart Dmax was greater for adapted plans (sched: 3.1 Gy/fx, adap: 3.3 Gy/fx; p = 0.013); 1 scheduled plan did not meet criteria. TIV was greater for the first 2 pt (median: 55 min) versus the final 2 pt (median: 42 min) [ p = 0.013]. While pt TIV was longer for fx 1 (median [min]: 66) than fx 5 (42), there were no differences in TIV between fx 2 (52), 3 (53), or 4 (52) versus fx 5. Addition of single breath-hold (SBH) CBCT acquisition led to a non-significant improvement in TIV (w/o SBH: 59 min, w/ SBH: 51 min; p = 0.058), non-significant improvement in mean PTV V100% (adap: 95.3%, SBH adap: 96.1%; p = 0.09), and did not affect OAR Dmax (adap: 5.2Gy/fx, SBH adap: 4.5Gy/fx; p = 0.19). CT-ART SBRT for liver tumors is feasible. In this series, adapted plans increased PTV coverage and ITV coverage. Among all cases, adapted plans improved mean stomach Dmax, improved mean small bowel Dmax, and increased mean heart Dmax. Among instances of PTV-OAR overlap, adapted plans improved mean PTV coverage and decreased OAR Dmax. [ABSTRACT FROM AUTHOR]

Delivering adequate doses to the target while sparing surrounding radiosensitive organs presents a challenge for unresectable pancreatic cancer. Planning Bragg peak proton FLASH therapy has yet to be studied but can allow for precise delivery of ablative doses to the target area while maintaining an ultra-high dose rate, potentially offering additional protection to adjacent organs-at-risk (OARs) through the FLASH-sparing effect. Through a combined optimization of target coverage and FLASH dose ratios of OARs based on a phenomenological FLASH-sparing modeling, toxicities may be reduced. We hypothesize that the innovative Bragg peak FLASH technique can escalate the target dose, improve tumor control while maintain acceptable expected toxicity levels. Phenomenological FLASH-sparing modeling for different types of tissues sourced from existing literature was applied to simulate the FLASH-sparing effect. We used an in-house treatment planning system incorporating a FLASH biological optimization (FBO) module using the single-energy Bragg peak technique. Seven consecutive pancreatic cancer patients previously treated with conventional proton pencil beam scanning (CONV-IMPT) were reoptimized, with the target dose intentionally escalated from 40 Gy to 50 Gy in 5 fractions with both methods. Dose metrics for OARs according to AGITG and TROG guidelines were compared. Table 1 illustrates the doses to major OARs of a 40 Gy in 5 fractions regimen. The stomach, duodenum, and bowel are similar between CONV-IMPT and Bragg peak proton FLASH. The D0.5cc for the stomach, duodenum, and small bowel are 30.3 Gy, 32.6 Gy, and 14.2 Gy respectively, for clinical plans and 32.4 Gy, 38.8 Gy, and 3.9 Gy for Bragg peak plans. Escalating the target dose to 50 Gy without FBO leads to D0.5cc exceeding constraints, at 39.1 Gy for stomach, 48.5 Gy for stomach PRV, 44.7 Gy for duodenum, and 49.3 Gy for duodenum PRV. Conversely, with FBO, all D0.5cc values for OARs meet constraints. With innovative Bragg peak technique, incorporating FBO elevates the target dose, improves tumor control while potentially achieving reduced toxicities. [ABSTRACT FROM AUTHOR]

Trimodality therapy (TMT) for muscle invasive bladder cancer (MIBC) is an alternative to radical cystectomy with comparable rates of local control and overall survival (OS). Recurrences are common after therapy, prompting a need to better understand failure patterns and contributing factors. Given the inherent variation in treating a dynamic bladder adjacent to dose-limiting organs-at-risk (OARs), a study of spatial and dosimetric aspects of treatment is warranted. We evaluated patients treated with definitive TMT for MIBC, with a specific focus on spatial and dosimetric factors that may underlie failure patterns. We analyzed a database of TMT patients treated at a single institution from September 2014 to January 2023, conducting a retrospective review of treatment, radiographic, and clinical factors. Detailed radiation planning and dosimetric information, including dose to targets and OARs relative to prescription. Pre-treatment disease and local recurrences were mapped to six bladder wall regions defined by EAU endoscopy guidelines. We identified 43 patients with MIBC who underwent curative intent TMT, with 88% (39) having at least one available biopsy. Prescription dose varied between 45 and 64.8 Gy delivered in 1.80 to 2.75 Gy fractions. Three- and five-year OS were 62% and 36%, with 24 patients alive by the study end. 51% (22) of patients were treated with 3D-CRT, 44% (19) were treated with IMRT, and 5% (2) with a hybrid approach. Concurrent chemotherapies were mostly 5-fluorouracil / Mitomycin-C (53%) or gemcitabine (35%). 47% (22) of patients had repeat TURBT prior to chemoRT. The posterior (37%) and lateral (51% right, 35% left) walls were the most common sites of involvement, while the dome (23%) and trigone (21%) were least common. 11 patients failed locally with median time to failure (TTF) of 11.6 months. 13 patients failed distantly with median TTF of 11.3 months. 23% (10) of patients had a history of non-bladder cancer and 21% (9) had prior non-MIBC. 60% of patients were current or former tobacco users with a median of 30 pack-years. Of 11 local failures, 82% (9) had at least partial regional overlap to the treated primary. Dosimetric analysis of patients with local failure shows a median GTV D95% of 99.6% (96.8-100.7%), CTV D95% of 97.7% (93.6-102.0%), and PTV D95% of 98.2% (84.3-101.2%). The median D1% of the rectum was 99.9% (62.5-104.6%), the sigmoid 101% (95.9-104.5%), and the small bowel was 80.9% (5.2-104.4%). Local failure after TMT is common, with a significant proportion of recurrences occurring at or near the site of pre-treatment disease. As we observed a large range in target and OAR dose, further investigation is warranted to determine whether superior local control may be achieved through altered spatial and dosimetric considerations without additional toxicity. Additionally, identifying molecular correlates of failure patterns may also provide valuable insights into the response to TMT and guide personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Organ at risk (OAR) dose constraints are critical to minimize toxicity from radiation treatment (RT). There is limited evidence supporting optimal pelvic OAR constraints, resulting in heterogeneity across clinical trials involving pelvic disease sites. OAR dose constraints used in major clinical trials of conventionally fractionated RT (CFRT) for pelvic diseases were systematically evaluated to propose their consolidation to improve treatment planning efficiency and encourage standardization. Site-specific directives providing guidance on treatment planning, including dose constraints, are used in our system to standardize treatment. A systematic review of the literature from 2014-2024 was conducted in PubMed and Embase following the PRISMA guidelines to identify Phase II-III clinical trials for CFRT RT across pelvic disease sites conducted by large cooperative groups. Articles were imported into Covidence and reviewed by two reviewers. OAR constraints were derived from these manuscripts. All recommended OAR dose values were binned and the most frequent value for each dose level was assigned as the mandatory constraint. The proposed constraints were reviewed by our protocol directives committee and approved for use across our system. Of the 619 screened studies, 121 phase II-III cooperative group trials met our inclusion criteria. Nine additional studies were manually added. In compliance with AAPM TG-263 and to facilitate future data pooling efforts OARs were defined as: Rectum, Bowel_Bag, Bowel_Large, Bowel_Small, Femur_L/R, Bladder, and Colon_Sigmoid. We were able to consolidate 10 total sets of OAR constraints across pelvic CFRT directives to only one shown in the Table. We found no standardization of OAR dose constraints used in clinical trials evaluating CFRT in pelvic diseases. This variability in OAR dose constraints creates challenges in creating a uniform standard of care for cancer patients. We developed a uniform set of OAR constraints to use across all pelvic disease sites to standardize our treatment planning process. We hypothesize that this will enhance efficiency across the radiation clinics in our system. We plan to test this hypothesis by analyzing treatment planning duration before and after the implementation of this process change. * Planning constraint when brachytherapy boost will follow Abbreviations: Gy, Gray; cc, cubic centimeter; n/a, not applicable [ABSTRACT FROM AUTHOR]

There are limited data regarding the efficacy of radiotherapy for treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Radiotherapy can be used for treatment of unresectable primary tumors or for targeting solitary metastatic sites. The efficacy and toxicity in the use of high biologic effective dose (BED 10) MRI-guided radiotherapy (MRgRT) for GEP-NETs is unknown. An IRB approved, single-institution retrospective study was performed of patients with diagnosis of GEP-NET treated with MRgRT from 2019 - 2023 to any site of disease. Clinical outcomes of interest included overall survival (OS) from date of diagnosis and progression free survival (PFS) and local control (LC) calculated from date of MRgRT. Acute and late radiation toxicity (CTCAE version 5.0) was characterized as less than or greater than 90 days from MRgRT, respectively. A total of 21 patients were identified with a median follow up from MRgRT of 17 months (IQR [12 – 33]). The median age was 55 years with most primary tumors located in the pancreas (71.4%), 5 (23.8%) in the small bowel, 1 (4.8%) in the ampulla, and 1 unknown. 19 (90.5%) patients were metastatic at the time of MRgRT. The MRgRT target was an abdominal lymph node in 11 (52.4%), pancreas in 5 (23.8%), liver in 4 (19.0%), and synchronous treatment of the pancreas and a lymph node in 1. The median biologically equivalent dose (BED 10) delivered during MRgRT was 100 Gy (IQR [76.7, 132]). 4 patients (19.0%) reported acute or late MRgRT toxicity; 2 (9.5%) reported acute Grade 3 toxicity and 1 had late MRgRT toxicity in the form of Grade 2 leuko/lymphopenia. The median OS and LC were not reached; 1 patient had local failure at 16 months resulting in a crude local control rate of 95.2%. Median PFS was 25 months (95% CI [16, Not reached]). BED 10 > 100 did not significantly correlate with Grade 3 toxicity (p = 0.07). MRgRT was well tolerated in this cohort of GEP-NET patients and LC was excellent across all tumor classifications. Because of the relative indolent biology of GEP-NETs, mitigation of late toxicity may be best approached with MRgRT and these outcomes should be updated with additional follow up. MRgRT should be considered as a reasonable option for patients unsuitable for primary tumor resection or metastasectomy. [ABSTRACT FROM AUTHOR]

The standard of care for well-differentiated, grade 1-2 GEP-NETs after somatostatin analog therapy includes 177Lu-DOTATATE based on the results of the landmark NETTER-1 trial. A subgroup analysis demonstrated a reduction in 12-month progression free survival (PFS) from 95% to 75% in the presence of a lesion larger than 3 cm. We performed a retrospective review to characterize the distribution of disease and assess the impact of tumor size on PFS. This single institution, retrospective study was IRB approved. Inclusion criteria included progressive, advanced GEP-NETs treated with 177Lu-DOTATATE between 2018 and 2022. Patients who did not complete 4 cycles of therapy were excluded. Diagnostic imaging immediately preceding 177Lu-DOTATATE and at the time of progression was reviewed. The size and location of the largest tumor prior to therapy was recorded and, when applicable, patterns of progression were assessed. The Kaplan-Meier method was used to assess PFS following 177Lu-DOTATATE. The impact of tumor size was assessed using the Cox Proportional Hazards and Wilcoxon test. A total of 120 patients were included in this analysis. Primary tumors of the small bowel (44%) and pancreas (36%) were most common but rectal (6%), appendiceal (1%), and unknown primaries (13%) were also included. Well-differentiated tumors predominated (83%) and differentiation was unknown in 16%. In general, this was a more heavily pre-treated population compared to NETTER-1 with 50% undergoing resection of the primary, 50% receiving two or more lines of systemic therapy, and 22% receiving liver-directed therapy. Prior to 177Lu-DOTATATE, metastases were identified in the liver (95%), lymph nodes (73%), and bone (34%). The mean size of the largest recorded tumor was 4.6 cm (standard deviation 2.81 cm). The largest tumor was most often found in the liver (70%) but mesenteric lymph node conglomerates (17%) and primary sites (6%) were also identified. With a median follow-up of 14 months (range = 0.3-56), the 12-month PFS was 76%. Increasing tumor size was associated with inferior PFS (hazard ratio 0.12, 95% confidence interval 0.01- 0.21, p = 0.03). For those with tumor sizes exceeding 3 cm (n = 73, 61%), the 12-month PFS was 69% compared to 84% for those with smaller tumors (p = 0.15). If tumor size exceeded 6 cm (n = 28, 23%), the 12-month PFS was 57% versus 82% (p = 0.04). Of the 47 patients who progressed, 60% were found to have progression in the largest lesion. In those without progression in the large lesion, progression was noted in a new lesion in 38% and the primary in 2%. Increasing tumor size is a negative prognostic factor for PFS after 177Lu-DOTATATE. Disease progression in the largest lesion is common. Strategies to improve outcomes in patients with large GEP-NET lesions are needed. [ABSTRACT FROM AUTHOR]

Biology-guided radiotherapy (BgRT) with fluorodeoxyglucose (FDG) signal collected via an on-board positron emission tomography (PET) system integrated in an O-ring gantry Linac was cleared by the Food and Drug Administration (FDA) for lung and bone lesions. This study aims to determine if BgRT is feasible in the liver, an organ which has a FDG signal background, and if plans are clinically acceptable for FDG-avid metastatic liver lesions. Ten patients with metastatic liver lesions were retrospectively selected from one academic institution. Diagnostic PET/CT images of these treatment sites were collected and resampled to match the CT used for planning. Diagnostic PET images were converted to mimic PET images that are acquired on a PET-Linac and would be used to guide the delivery. For BgRT planning, the planned tumor volume (PTV) was generated with 5 mm margin from gross tumor volume (GTV) and a Biology Tracking Zone was generated including the anticipated full range of target motion. BgRT plans were created to 36Gy in 4 fractions for liver lesions. BgRT plan creation was first tested to determine if the Activity Concentration (AC) and Normalized Target Signals (NTS) on converted PET images would meet BgRT AC and NTS hard constraints required for plan creation. GTV and PTV were collected. BgRT plan quality was then evaluated for PTV coverage, including V100%, D98% and mean Dose (Dmean), PTV point dose (Dmax), conformity index (CI) and Heterogeneity index (HI), and organ at risk (OAR) mean doses. Six lesions met the constraints for NTS and AC for plan creation in four patient datasets. The average GTV size was 14.9 +/- 10.4 cc, with a PTV of 35.8 +/- 21.0 cc. The diagnostic PET PTV mean AC, liver mean AC, and derived AC and NTS on converted PET images average and standard deviation were 16.6 +/- 3.2 kBq/ml, 9.6 +/-1.3 kBq/ml, 13.97 +/- 2.89 kBq/ml and 6.85 +/- 3.16, respectively. All plans met OAR dose constraints such as max dose on duodenum, ribs, skin, small bowel, and stomach. For the six plans, lesion PTV coverage, V100%, D98%, and Dmean were 91.02 +/- 5.59%, 34.8 +/- 1.5 Gy and 39.5+/- 1.3 Gy. The PTV Dmax, CI and HI were 124.8 +/-10.2%, 1.13+/- 0.04 and 1.25+/-0.10. The Dmean for Liver minus PTV, right rib, right lung, stomach, duodenum and small bowel were 7.2 +/- 2.0, 2.2 +/- 0.5, 0.5 +/-0.8, 2.4 +/-1.4, 1.4 +/- 1.4 and 0.4 +/- 0.2 Gy, respectively. This initial study demonstrates the feasibility of BgRT planning for liver lesions, indicating successful adherence to AC and NTS constraints, and satisfactory plan quality meeting clinical requirements. [ABSTRACT FROM AUTHOR]

Low anterior resection syndrome (LARS) can occur after surgical resection of rectal cancer and is more frequent after preoperative radiation (RT). We hypothesized RT dose to the sigmoid colon and anal sphincter complex, in addition to the small bowel, could impact the function of the postoperative anatomy. In this study, we retrospectively evaluated radiation plans of patients who did and did not experience LARS syndrome after multimodality therapy for locally advanced rectal cancer and sought to identify potential dosimetric predictors of LARS. We identified patients with rectal cancer treated with long-course chemoRT (LC-CRT; 50.4Gy in 28 fractions) at our institution from 2016–2020 who were alive without disease. We administered a patient-reported outcomes (PRO) survey that included the LARS instrument for patients without an ostomy at the time of the survey. We then accessed their RT treatment plans and contoured the sigmoid colon, small bowel and the anal sphincters (approximated as two centimeters proximal to the anal verge). We collected mean dose, maximum dose and V5-V50 Gy at 5 Gy increments for each structure. We then performed a logistic regression to evaluate the potential relationships between the dosimetric variables and overall LARS score, as well as the individual LARS symptom items for flatus, leakage, frequency, clustering and urgency. Of 110 patients treated with preoperative-intent LC-CRT who did not have an ostomy at the time of survey, 57 responded (51.8%). Sixteen had a complete clinical response and did not have surgery. Thirty-nine were treated with a low anterior resection and were included in this analysis. The median [IQR] interval between RT and survey was 13.5 [29.7-49.0] months. The median [IQR] age of patients was 55 [49.5-62.5], 24 (61.5%) were male, 31 (79.5%) had T3 tumors, 35 (89.7%) had N+ disease, 34 (87.2%) were treated with 3D conformal RT and 36 (92.3%) were treated in the prone position. The median [IQR] LARS score was 34 [29-39], and 27 (69.2%) qualified as Major LARS (score 30-42). Twenty-four (61.5%) patients had incontinence of flatus at least once a week, 27 (69%) experienced incontinence/leakage of liquid stool, 18 (46.2%) had 4-7 bowel movements (BM) per day, 5 (12.8%) had > 7 BMs per day, 31 (79.5%) had to move their bowels within an hour of the last BM. All but one patient (97.4%) had urgent BMs such that they have to rush to the toilet, and 23 (59.0%) had these urgency episodes more than once per week. None of the dosimetric variables significantly correlated with numeric LARS score, Major LARS category, or any of the LARS symptom items. We were unable to identify small bowel, sigmoid or anal sphincter dosimetric predictors of LARS score or major LARS category in this cohort of patients treated with preoperative LC-CRT. Further study is warranted to explore the potential relationship between radiation dose to key pelvic OARs and patient-reported functional outcomes. [ABSTRACT FROM AUTHOR]

Radiation induced intestine injury significantly limits the application of radiotherapy in treating abdominal and pelvic malignancies. Intestinal macrophages constantly differentiate and polarize coincide with microbe metabolites, yet little is known how macrophage and microbiota orchestrate in shaping the outcome of radiation induced intestine injury. Intestinal resident CX3CR1+ macrophages are derived from embryos and replenished from peripheral circulating monocytes through a "monocyte waterfall" process depending on CCL2/CCR2 axis. The turnover kinetics and function of intestinal resident macrophage subpopulations governed by microbiota during radiation and the underlying mechanisms remains poorly defined. Herein, we used genetic modified mouse Ccr2+/+ Cx3cr1+/+ (WT), Ccr2RFP/RFPCx3cr1+/+ (R2-KO) and Ccr2+/+Cx3cr1GFP/GFP(X3-KO) mice in Abx treated murine radiation induced intestine injury model. Mice were exposed to abdominal radiation of 13 Gy to induce radiation enteritis. Broad-spectrum antibiotics model (Abx model: ampicillin, neomycin, vancomycin and metronidazole) were used to investigate the functions of microbiota in regulating radiation enteritis. Severity of injury were evaluated and compared among groups through HE staining, immunohistochemistry, and electron microscope. Lamina propria immune cells were analyzed by flowcytometry. The gut microbiome from fresh fecal samples were detected by 16S rDNA sequencing, and the metabolites were detected by GC‒MS analysis. Ionizing radiation increased the number of macrophages and co-expression of CCR2 and CX3CR1 in luminal propria, while does not alter the CD86/CD206 (M1/M2) ratio. Deletion of either CCR2 (R2-KO) or CX3CR1(X3-KO) significantly ameliorated radiation induced intestine injury as suggested by intestine length, length of villi, number of crypts and epithelial thickness. Abx pretreatment attenuated radiation induced injury in small intestine and colon, restored the length of villi and number of goblet cells. Recruitment of circulating monocytes to luminal propria macrophages pool after ionizing radiation relies on gut microbiota in that number of CCR2+ cells were significantly decreased in Abx treatment group. Notably, the turnover kinetics of CX3CR1lo to CX3CR1int macrophages and proportion of CD4+FoxP3+ was further upregulated in Abx treatment group. Mechanistically, Abx treatment enriched galactose-producing bacteria such as Ligilactobacillus, indicated by 16s rDNA. In addition, metabolomic profiling analysis suggested Abx-induced metabolic reprogramming, especially Biochanin A 7-sulfate enrichment in intestine. Radiation induced intestinal resident macrophages turnover from CX3CR1lo to dendritic-like CX3CR1int macrophages is orchestrated by microbiota. Preferential supplement of microbiota and metabolites may provide novel insight to mitigate radiation induced intestine injury. [ABSTRACT FROM AUTHOR]

A recent phase III clinical trial at a single institute has demonstrated that aggressive margin reduction with MRI-guided prostate SBRT decreased acute grade ≥ 2 genitourinary (GU) and gastrointestinal (GI) toxicity following prostate SBRT, as compared against CT-guidance. We hypothesized that toxicity reduction could be attributable to decreased radiation exposure to nearby urinary and bowel structures. Herein, we evaluate the dosimetric impact of margin reduction on relevant GU and GI organs-at-risk (OARs) and its association with GU and GI toxicity. One-hundred-and-fifty-six patients were randomized to CT-guided (4 mm PTV-expansion) or MR-guided (2 mm PTV-expansion) prostate SBRT (40 Gy in 5 fractions). Dosimetric statistics (D0.035cc, V40Gy, V39Gy, V20Gy) for relevant OARs (bladder, rectum, and small bowel) were calculated on pre-treatment simulation images. Physician-scored acute (0-3 months) and late (>3-24 months) GU and GI toxicity (CTCAE v4.03 scale) were evaluated. Statistical significance was assessed using two-sided, unpaired t-tests with level of significance set at 0.05. High dose radiation to the bladder was significantly decreased with MRI-guided treatment compared to CT-guided treatment (D0.035cc, V40Gy and V39Gy, p < 0.05). Rectal dosimetry was comparable between treatments regardless of hydrogel placement. Radiation to the small bowel (D0.035cc) trended lower in the MRI-guided treatment arm, but differences did not reach statistical significance. Regardless of treatment arm, bladder dose was higher in patients with acute (V20Gy, V39Gy, V40Gy, p<0.05) and late (V40Gy, p<0.05) grade ≥ 2 GU toxicity. Rectal dose trended higher in patients with acute and late grade ≥ 2 GI toxicity but failed to reach statistical significance. Small bowel dose was higher in patients with acute grade ≥ 2 GI toxicity (D0.035cc and V20Gy, p<0.05) and trended higher in those with late grade ≥ 2 GI toxicity. Aggressive margin reduction results in significantly lower dose to the bladder, and regardless of margin, higher bladder doses were associated with acute and late toxicity. A similar, though less marked, association was seen for small bowel dosimetry. In contrast, rectal dosimetry was not significantly different between arms, though increased rectal dose trended towards association with acute and late toxicity. These results suggest that while margin reduction might explain the significant differences in GU toxicity, dosimetry alone may not account for the large differences seen in GI toxicity. Limitations include analysis of discrete dosimetric parameters and planned dose. [ABSTRACT FROM AUTHOR]

Numerous studies have shown that arsenic (As) is an important hazardous metalloid that is commonly considered to have systemic toxicity. The main pathway of arsenic exposure is oral; however, many of the events that occur during its passage through the gastrointestinal tract are unclear, and there are few reports on the effect of arsenic on small intestinal mucosal barrier. This study aimed to investigate arsenic-induced mucosal barrier damage in the small intestine of mice induced by oral exposure and its potential mechanisms. In the present study, histomorphometric and immunohistochemical analyses showed that arsenic-treated mice exhibited signs of irregularly arranged and atrophied small intestinal villi, reduced villus lengths, inflammatory cells infiltration, along with up-regulated expression of inflammatory factors TNF-α, IL-6 and IL-1β in the small intestine of mice. The myeloperoxidase (MPO) activity was also increased in As-exposed mice. Transmission electron microscopy (TEM) analysis demonstrated that intestinal epithelial tight junctions (TJs) were impaired in the small intestines of mice in As group. In addition, arsenic down-regulated mRNA levels of TJ-related genes (ZO-1, ZO-2 , occludin , claudin-1 , and claudin-7) and protein levels of ZO-1, occludin and claudin-1 were significantly reduced in arsenic-treated groups, while arsenic also increased levels of TLR4, Myd88, NF-κB, RhoA, and ROCK mRNA and protein expression. In summary, these results indicate that the small intestine toxicity in mice evoked by arsenic was correlated with the activation of TLR4/Myd88/NF-κB and RhoA/ROCK pathways. • Arsenic intake induced inflammation and barrier damage in small intestinal tissue of mice. • Arsenic could trigger inflammatory response via the TLR4/Myd88/NF-κB pathway. • Arsenic could induce small intestinal TJ damage via the RhoA/ROCK pathway. [ABSTRACT FROM AUTHOR]

• Hemorrhage of undetermined origin is defined as a hemorrhage of intestinal origin for which no cause has been identified after esogastroduodenal endoscopy and total colonoscopy. • If there is no suspicion of intestinal obstruction, capsule endoscopy is the first-line examination. • CT-enteroclysis is performed as a first-line diagnostic study if an associated intestinal obstruction is suspected. • Enteroscopy is offered as a second-line treatment if the bleeding has been localized and is accessible to endoscopic treatment. Gastrointestinal bleeding of undetermined origin (GBUO) is defined as gastrointestinal bleeding without an identified cause or location despite an endoscopic assessment including an esogastroduodenal endoscopy (EOGD) and a total colonoscopy. A distinction is made between exteriorized GBUO and non-exteriorized occult GBUO. The causes in the majority of cases (vascular, inflammatory and tumoral) are located in the small intestine. The diagnostic strategy aiming to locate the origin of the GBUO is a real challenge. Innovation in endoscopic and imaging techniques has enabled minimally invasive exploration of the small intestine. In Europe, there is a strong consensus to recommend a video-capsule endoscopy (VCE) as the first-intention study. If there is reason to suspect intestinal obstruction, VCE is contraindicated and a CT-enteroscopy is then performed as first intention. Enteroscopy is performed as a second-line treatment, either for therapeutic purposes after a positive VCE or CT-enteroclysis, or for diagnostic purposes after a negative VCE. Finally, intraoperative enteroscopy (IOE) coupled with surgical exploration should be reserved either for therapeutic purposes in the event of impossibility or failure of preoperative enteroscopy, or for diagnostic purposes in the event of recurrent GBUO after failure of all other studies and explorations of the small intestine. [ABSTRACT FROM AUTHOR]

Migraine is a complex neurogenic inflammatory disorder. There are strong neuronal, endocrine, and immunologic connections between the brain and gastrointestinal system. Damage to the intestinal barrier is thought to cause systemic immune dysregulation. Zonulin is a protein produced by the small intestine epithelium in humans that regulates intestinal permeability through intracellular tight junctions and is a potential marker for inflammation. Zonulin increases in positive correlation with permeability. In our study, we aimed to research the correlation between serum zonulin levels in the period between attacks in pediatric patients with migraine. The study included 30 patients with migraine and 24 healthy controls, matched in terms of sex and age. Demographic and clinical characteristics were recorded. Serum zonulin levels were studied with the enzyme-linked immunosorbent assay method. Patients had a mean of 5.6 ± 3.5 attacks per month. The mean serum zonulin was 5.68 ± 1.21 ng/mL in the migraine group and 5.72 ± 2.1 ng/mL in the control group with no significant difference found (P = 0.084). In the migraine group, no correlations were identified between serum zonulin levels and age, body mass index, pain frequency, pain duration, onset time, visual analog scale score, and presence of gastrointestinal systems apart from nausea-vomiting. More than 50 proteins were identified to affect the intestinal permeability apart from zonulin. There is a need for prospective studies encompassing the time of attack, but our study is important as it is the first study about zonulin levels in pediatric migraine. [ABSTRACT FROM AUTHOR]