Acute Gastrointestinal Research Articles

Acute toxicity and quality of life in prostate cancer patients treated with definitive hypofractionated pelvic radiation therapy: a single-center report.

The objective was to report acute toxicity and quality of life in prostate cancer patients treated with definitive hypofractionated pelvic radiation therapy. Patients were designated candidates for hypofractionated pelvic radiation therapy if biopsy or imaging studies evidenced unfavorable intermediate-risk, high-risk or node-positive disease. Patients were treated using a regimen of 44 Gy to the nodal areas and simultaneous integrated boost of 60 Gy to the prostate in 20 fractions with CBCT-based imaging and volumetric arc therapy (VMAT). Patient data was obtained retrospectively; acute gastrointestinal (GI) and genitourinary (GU) toxicity was classified per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and obtained from clinical records. Quality of life was surveyed via phone call using the European Organization for Research and Treatment of Cancer (EORTC) questionnaire QLQ-PR25. 78 patients were treated between May and December 2021. 83.33% of patients had high-risk disease, 16.67% had intermediate-risk disease, and 34.62% patients had node-positive disease. Median follow-up was 10.6 months. No patients presented acute grade >3 GI toxicity, and one patient presented grade 3 GU toxicity. 25.64% patients presented acute G2 GI toxicity and 17.95% patients presented acute G2 GU toxicity. 60.26% of patients responded to the EORTC-PR25 questionnaire. Mean scores for symptom scales were 11.26, 4.96 and 9.57 for Urinary Symptoms, Bowel Symptoms and Hormonal Treatment-Related Symptoms; mean scores for Sexual Activity and Functioning were 19.86 and 31.08, respectively. Definitive hypofractionated pelvic radiation therapy has an acceptable acute toxicity and QoL profile in this series of patients, although longer follow-up is needed to properly evaluate short and long-term toxicity. Further follow-up and patient recruitment is ongoing.

Assessing the toxicity after moderately hypofractionated prostate and whole pelvis radiotherapy compared to conventional fractionation.

To evaluate acute and late gastrointestinal (GI) and genitourinary (GU) toxicities after moderately hypofractionated (HF) or conventionally fractionated (CF) primary whole-pelvis radiotherapy (WPRT). Primary prostate-cancer patients treated between 2009 and 2021 with either 60 Gy at 3 Gy/fraction to the prostate and 46 Gy at 2.3 Gy/fraction to the whole pelvis (HF), or 78 Gy at 2 Gy/fraction to the prostate and 50/50.4 Gy at 1.8-2 Gy/fraction to the whole pelvis (CF). Acute and late GI and GU toxicities were retrospectively assessed. 106patients received HF and 157 received CF, with amedian follow-up of 12and 57months. Acute GI toxicity rates in the HF and CF groups were, respectively, grade2: 46.7% vs. 37.6%, and grade3: 0% vs. 1.3%, with no significant difference (p = 0.71). Acute GU toxicity rates were, respectively, grade2: 20.0% vs. 31.8%, and grade3: 2.9% vs. 0%, (p = 0.04). We compared prevalence of late GI and GU toxicities between groups after 3,12, and 24months and did not find any significant differences (respectively, p = 0.59, 0.22, and 0.71 for GI toxicity; p = 0.39, 0.58, and 0.90 for GU toxicity). Moderate HF WPRT was well tolerated during the first 2years. Randomized trials are needed to confirm these findings.

Trimodal Therapy Using an MR–guided Radiation Therapy Partial Bladder Tumor Boost in Muscle Invasive Bladder Cancer

Bladder preservation with trimodal therapy (TMT; maximal tumor resection followed by chemoradiation) is an effective paradigm for select patients with muscle invasive bladder cancer. We report our institutional experience of a TMT protocol using nonadaptive magnetic resonance imaging-guided radiation therapy (MRgRT) for partial bladder boost (PBB). A retrospective analysis was performed on consecutive patients with nonmetastatic muscle invasive bladder cancer who were treated with TMT using MRgRT between 2019 and 2022. Patients underwent intensity modulated RT-based nonadaptive MRgRT PBB contoured on True fast imaging with steady state precession (FISP) images (full bladder) followed sequentially by computed tomography-based RT to the whole empty bladder and pelvic lymph nodes with concurrent chemotherapy. MRgRT treatment time, table shifts, and dosimetric parameters of target coverage and normal tissue exposure were described. Prospectively assessed acute and late genitourinary and gastrointestinal (GI) toxicity were reported. Two-year local control was assessed with Kaplan-Meier methods. Seventeen patients were identified for analysis. PBB planning target volume margins were ≤8 mm in 94% (n=16) of cases. Dosimetric target coverage parameters were favorable and all normal tissue dose constraints were met. For MRgRT PBB fractions, median table shifts were 0.4 cm (range, 0-3.15), 0.45 cm (0-2.65), and 0.75 cm (0-4.8) in the X, Y, and Z planes, respectively. Median treatment time for MRgRT PBB fractions was 9 minutes (range, 6.9-17.4). We identified 32 out of 100 total MRgRT fractions that may have benefitted from online adaptation based on changes in organ position relative to planning target volume, predominantly because of small bowel (13/32, 41%) or rectum (8/32, 25%). Two patients discontinued RT prematurely. The incidence of highest-grade acute genitourinary toxicity was 1 to 2 (69%) and 3 (6%), whereas the incidence of acute GI toxicity was 1 to 2 (81%) and 3 (6%). There were no late grade 3 events; 17.6% had late grade 2 cystitis and none had late GI toxicity. With median follow-up of 18.2 months (95% CI, 12.4-22.5), the local control rate was 92%, and no patient has required salvage cystectomy. Nonadaptive MRgRT PBB is feasible with favorable dosimetry and low resource utilization. Larger studies are needed to evaluate for potential benefits in toxicity and local control associated with this approach in comparison to standard treatment techniques.

From once-weekly to semi-weekly whole prostate gland stereotactic radiotherapy with focal boosting: Primary endpoint analysis of the multicenter phase II hypo-FLAME 2.0 trial

Background and purposeThe hypo-FLAME trial showed that once-weekly (QW) focal boosted prostate stereotactic body radiotherapy (SBRT) is associated with acceptable acute genitourinary (GU) and gastrointestinal (GI) toxicity. Currently, we investigated the safety of reducing the overall treatment time (OTT) of focal boosted prostate SBRT from 29 to 15 days. Material and methodsPatients with intermediate- and high-risk prostate cancer were treated with SBRT delivering 35 Gy in 5 fractions to the whole prostate gland with an iso-toxic boost up to 50 Gy to the intraprostatic lesion(s) in a semi-weekly (BIW) schedule. The primary endpoint was radiation-induced acute toxicity (CTCAE v5.0). Changes in quality of life (QoL) were examined in terms of proportions achieving a minimal clinically important change (MCIC). Finally, acute toxicity and QoL scores of the BIW schedule were compared with the results of the prior QW hypo-FLAME schedule (n = 100). ResultsBetween August 2020 and February 2022, 124 patients were enrolled and treated BIW. No grade ≥3 GU or GI toxicity was observed. The 90-days cumulative incidence of grade 2 GU and GI toxicity rates were 47.5% and 7.4%, respectively. Patients treated QW scored significant less grade 2 GU toxicity (34.0%, p = 0.01). No significant differences in acute GI toxicity were observed. Furthermore, patients treated QW had a superior acute bowel and urinary QoL. ConclusionSemi-weekly prostate SBRT with iso-toxic focal boosting is associated with acceptable acute GU and GI toxicity. Based on the comparison between the QW and BIW schedule, patients should be counselled regarding the short-term advantages of a more protracted schedule.Registration number ClinicalTrials.gov: NCT04045717.

Increased toxicities associated with dose escalation of stereotactic body radiation therapy in prostate cancer: results from a phase I/II study

Background This dose-escalation study evaluated the toxicity and efficacy of different stereotactic body radiation therapy (SBRT) doses for selecting an optimal dose for prostatic adenocarcinoma (PCa). Materials and methods This clinical trial was registered at UMIN (UMIN000014328). Patients with low- or intermediate-risk PCa were equally assigned to 3 SBRT dose levels: 35, 37.5, and 40 Gy per 5 fractions. The primary endpoint was the occurrence rate of late grade ≥2 genitourinary (GU) and gastrointestinal (GI) adverse events at 2 years, while the secondary endpoint was the 2-year biochemical relapse-free (bRF) rate. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Results Seventy-five patients (median age, 70 years) were enrolled from March 2014 to January 2018, of whom 10 (15%) and 65 (85%) had low- and intermediate-risk PCa, respectively. The median follow-up time was 48 months. Twelve (16%) patients received neoadjuvant androgen deprivation therapy. The 2-year occurrence rates of grade 2 late GU and GI toxicities were 34 and 7% in all cohorts, respectively (35 Gy: 21 and 4%; 37.5 Gy: 40 and 14%; 40 Gy: 42 and 5%). The occurrence risk of GU toxicities significantly increased with dose escalation (p = 0.0256). Grades 2 and 3 acute GU toxicities were observed in 19 (25%) and 1 (1%), respectively. Grade 2 acute GI toxicity was observed in 8 (11%) patients. No grade ≥3 GI or ≥4 GU acute toxicity or grade ≥3 late toxicity was observed. Clinical recurrence was detected in 2 patients. Conclusions An SBRT dose of 35 Gy per 5 fractions is less likely to cause adverse events in patients with PCa than 375- and 40-Gy SBRT doses. Higher doses of SBRT should be applied with caution.

Citrulline, Intestinal Fatty Acid-Binding Protein and the Acute Gastrointestinal Injury Score as Predictors of Gastrointestinal Failure in Patients with Sepsis and Septic Shock.

Gastrointestinal (GI) failure can be both a cause of sepsis and a consequence of the systemic pro-inflammatory response in sepsis. Changes in biomarkers of enterocyte damage, citrulline and I-FABP (intestinal fatty acid binding protein), may indicate altered intestinal permeability and damage. The study group consisted of patients with sepsis (N = 28) and septic shock (N = 30); the control group included patients without infection (N = 10). Blood samples were collected for citrulline and I-FABP and a 4-point AGI score (acute GI injury score) was calculated to monitor GI function on days 1, 3, 5, 7, and 10. Citrulline concentrations in the study group were lower than in the control. Lower values were also noted in septic patients with shock when compared to the non-shock group throughout the study period. I-FABP was higher in the septic shock group than in the sepsis group only on days 1 and 3. Citrulline was lower in patients with GI failure (AGI III) when compared to AGI I/II, reaching significance on days 7 (p = 0.034) and 10 (p = 0.015); moreover, a higher AGI score was associated with an increased 28 day mortality (p = 0.038). The results indicate that citrulline measurements, along with the AGI assessment, have clinical potential in monitoring GI function and integrity in sepsis.

Gut enterochromaffin cells drive visceral pain and anxiety.

Gastrointestinal (GI) discomfort is a hallmark of most gut disorders and represents an important component of chronic visceral pain1. For the growing population afflicted by irritable bowel syndrome, GI hypersensitivity and pain persist long after tissue injury has resolved2. Irritable bowel syndrome also exhibits a strong sex bias, afflicting women three times more than men1. Here, we focus on enterochromaffin (EC) cells, which are rare excitable, serotonergic neuroendocrine cells in the gut epithelium3-5. EC cells detect and transduce noxious stimuli to nearby mucosal nerve endings3,6 but involvement of this signalling pathway in visceral pain and attendant sex differences has not been assessed. By enhancing or suppressing EC cell function in vivo, we show that these cells are sufficient to elicit hypersensitivity to gut distension and necessary for the sensitizing actions of isovalerate, a bacterial short-chain fatty acid associated with GI inflammation7,8. Remarkably, prolonged EC cell activation produced persistent visceral hypersensitivity, even in the absence of an instigating inflammatory episode. Furthermore, perturbing EC cell activity promoted anxiety-like behaviours which normalized after blockade of serotonergic signalling. Sex differences were noted across a range of paradigms, indicating that the EC cell-mucosal afferent circuit is tonically engaged in females. Our findings validate a critical role for EC cell-mucosal afferent signalling in acute and persistent GI pain, in addition to highlighting genetic models for studying visceral hypersensitivity and the sex bias of gut pain.

The Association between Acute and Late Genitourinary and Gastrointestinal Toxicities: An Analysis of the PACE B Study

Several studies have demonstrated the association between acute and late radiotherapy toxicity in prostate cancer using older radiotherapy techniques. However, whether this association is present with newer techniques such as stereotactic body radiotherapy (SBRT), remains unclear. We use univariable and multivariable logistic regression to analyse the association between grade 2 or worse acute gastrointestinal (GI) and genitourinary (GU) toxicities with equivalent late toxicities in patients treated with SBRT and conventional or moderately fractionated radiotherapy (CRT) within the PACE-B study. 842 patients were included in this analysis. Common Terminology Criteria for Adverse Events (CTCAE) was the primary clinician reported outcome measure used in this analysis. In univariable analysis, experiencing a grade 2+ acute GU toxicity was significantly associated with developing a grade 2+ late GU toxicity after SBRT (OR 4.63, 95% CI (2.96-7.25), p < 0.0001) and CRT (OR 2.83, 95% CI (1.69-4.71), p < 0.0001). This association remained significant in multivariable analysis. In univariable analysis, experiencing a grade 2+ acute GI toxicity was also associated with developing a grade 2+ late GI toxicity after SBRT (OR 3.67, 95% CI (1.91-7.03), p < 0.0001) and CRT (OR 4.4, 95% CI (2.04-9.47), p < 0.0001). This association also remained significant in multivariable analysis. Grade 2+ baseline GU symptoms were also associated with grade 2+ late urinary toxicity in both univariable and multivariable analysis. Overall, acute toxicity is an important predictor variable for late GU/GI toxicity after localised prostate radiotherapy using SBRT and CRT. Future work should test whether optimising symptoms pre-treatment and early intervention in those with significant acute toxicities could mitigate the development late of toxicity.

Transcriptome analysis in acute gastrointestinal graft-versus host disease reveals a unique signature in children and shared biology with pediatric inflammatory bowel disease.

We performed transcriptomic analyses on freshly frozen (n=21) and paraffin-embedded (n=35) gastrointestinal (GI) biopsies from children with and without acute acute GI graft-versus-host disease (GvHD) to study differential gene expressions. We identified 164 significant genes, 141 upregulated and 23 downregulated, in acute GvHD from freshy frozen biopsies. CHI3L1 was the top differentially expressed gene in acute GvHD, involved in macrophage recruitment and bacterial adhesion. Mitochondrial genes were among the top downregulated genes. Immune deconvolution identified a macrophage cellular signature. Weighted gene co-expression network analysis showed enrichment of genes in the ERK1/2 cascade. Transcriptome data from 206 ulcerative colitis (UC) patients were included to uncover genes and pathways shared between GvHD and UC. Comparison with the UC transcriptome showed both shared and distinct pathways. Both UC and GvHD transcriptomes shared an innate antimicrobial signature and FCγ1RA/CD64 was upregulated in both acute GvHD (log-fold increase 1.7, P=0.001) and UC. Upregulation of the ERK1/2 cascade pathway was specific to GvHD. We performed additional experiments to confirm transcriptomics. Firstly, we examined phosphorylation of ERK (pERK) by immunohistochemistry on GI biopsies (acute GvHD n=10, no GvHD n=10). pERK staining was increased in acute GvHD biopsies compared to biopsies without acute GvHD (P=0.001). Secondly, plasma CD64, measured by enzyme-linked immunsorbant assay (n=85) was elevated in acute GI GvHD (P<0.001) compared with those without and was elevated in GVHD compared with inflammatory bowel disease (n=47) (P<0.001), confirming the upregulated expression seen in the transcriptome.

Effects of gold fiducial marker implantation on tumor control and toxicity in external beam radiotherapy of prostate cancer.

Evidence regarding the effects of fiducials in image-guided radiotherapy (IGRT) for tumor control and acute and late toxicity is sparse. Patients with primary low- and intermediate-risk prostate cancer, 40 with and 21 without gold fiducial markers (GFM), and treated between 2010 and 2015 were retrospectively included. The decision for or against GFM implantation took anaesthetic evaluation and patient choice into account. IGRT was performed using electronic portal imaging devices. The prescribed dose was 78 Gy, with 2 Gy per fraction. Biochemical no evidence of disease (bNED) failure was defined using the Phoenix criteria. Acute and late gastrointestinal (GI) and genitourinary toxicity (GU) were assessed using the Radiation Therapy Oncology Group criteria. Most patients did not receive GFM due to contraindications for anaesthesia or personal choice (60% and 25%). Regarding tumor control, no significant differences were found regarding bNED and overall and disease-specific survival (p = 0.61, p = 0.56, and p > 0.9999, respectively). No significant differences in acute and late GI (p = 0.16 and 0.64) and GU toxicity (p = 0.58 and 0.80) were observed. We were unable to detect significant benefits in bNED or in early or late GI and GU side effects after GFM implantation.

Effective management of acute gastrointestinal hemorrhage

Background: Gastrointestinal (GI) hemorrhage, a significant health concern particularly among the elderly, is a leading cause of hospital admissions for gastrointestinal disorders. The condition can be present as hematemesis, hematochezia, or melena, with varying etiologies based on the site of bleeding. Management of GI bleeding is complex and varies according to the stability of the patient and the source of bleeding. Aim: This article aims to review current approaches for the effective management of acute GI hemorrhage, focusing on diagnostic and therapeutic strategies employed by pharmacists and emergency medical services. Also, review will focus on the role of health information systems for the management and controlling GI hemorrhage in future responses. Methods: A comprehensive review of management practices was conducted, including initial evaluation, resuscitation strategies, and diagnostic procedures. Emphasis was placed on the roles of endoscopy, imaging studies, and multidisciplinary care in the management of both stable and unstable GI bleeding. Results: Effective management starts with hemodynamic stabilization and involves the use of crystalloid resuscitation and blood transfusions as needed. Endoscopy is preferred for stable cases of upper and lower GI bleeding, performed within 24 hours of presentation.

Spatial Transcriptomics of Tissue-Based Immune Response to Acute Graft-Versus-Host Disease of the Lower Gastrointestinal Tract

Background: Corticosteroid resistant acute graft-versus-host disease (GVHD) of the lower gastrointestinal (GI) tract is a leading cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. We hypothesized that distinct gene expression profiles exist within affected GI tissue at GVHD diagnosis and may be associated with treatment outcomes. Methods: Unstained tissue sections from 33 patients with biopsy-confirmed acute lower GI GVHD were used for spatial transcriptomics using the NanoString GeoMxTM Digital Spatial Profiler (DSP) platform. Fluorescent morphology markers (PanCK, CD45 and CD31) were used to visualize the epithelial, immune and endothelial compartments and guide capture of RNA expression profiles using the GeoMxTM Human Whole Transcriptome Atlas (18,676 genes). A total of 739 areas of interest (AOIs) were sampled across the 33 patients with a total of 57,960 immune, 37,610 epithelial, and 2298 vascular endothelial cells analyzed (average of 1756.4 immune, 1139.7 epithelial and 69.6 endothelial cells per case). The gene specific oligos were quantified using Illumina's i5 x i7 dual-indexing system and sequenced on the Illumina NextSeq 500 using a 2 x 75 MidOutput v2.5 flow cell. The FASTQ files were processed to generate target probe-specific count files and saved in DCC format. Gene expression files were normalized per NanoString protocol. All unsupervised clustering and differential expression were done in Bioconductor in the R statistical computing space. Results: The gene expression data for each AOI of immune, epithelial, and endothelial cells were normalized and the top 500 most variable genes were used for unsupervised hierarchical clustering to obtain an unbiased classification of different subtypes. There were two clear major AOI clusters for each of the cellular compartments with immune clustering shown in Figure 1A. The left immune cluster (IC1) and the right immune cluster (IC2) were then evaluated for association with clinical GVHD outcomes. IC1 had an over-representation of patients with steroid sensitive GVHD (Fisher exact p value = <0.0001) and AOIs with low grade pathology (Fisher exact p value = 0.031). To obtain gene level differences between IC1 and IC2, differential expression was performed using a Wilcoxon Rank Sum test and volcano plots were generated to illustrate the most differentially expressed genes across the visual AOI-based clusters (Figure 1B). Genes with an adjusted p-value of 0.05 for association with the particular arm of the volcano plot and at least a 2-fold change over the other cluster were considered significant. Gene set enrichment analysis (GSEA) using curated datasets from MSigDB was performed and identified that IC1 genes were enriched for IFNγ response (q value = 2.99e-5), TNFα signaling (q value = 2.99e-5) and inflammatory response (q value = 0.0063). These IC1 differentially expressed genes included CD74 (835 vs. 361.6 mean normalized gene transcripts), LYZ, β2-microglobulin, C1QB and CD68. IC2, on the other hand, had a prominent exhausted/immunosuppressive signature significantly enriched for Th17 cell genes (q value = 0.027) by GSEA. Notable genes that were statistically significant were FCF1 (152.3 vs. 74 mean normalized transcripts) and USP17L11 (78.3 vs. 36.4 mean normalized transcripts). Extension of this analysis to the epithelial (EC) and vascular endothelial (VC) cell compartments also identified distinct clustering with both having an inflamed (EC1 and VC1) and a basal-like state (EC2 and VC2). Interestingly, the inflamed epithelial cells (EC2) associated with immunosuppressive IC2 immune cells (Fisher exact p-value = 0.006), but inflamed vascular endothelium (VC1) associated with the pro-inflammatory IC1 immune cells (Fisher exact p-value = 0.0005). Conclusion: Spatial transcriptomics provides high resolution gene expression profiles in distinct cellular compartments in human acute GI GVHD samples and provides a better understanding of the relationship of the immune response with epithelial and vascular endothelial cell phenotypes. Initial analysis demonstrates that an inflammatory immune signature is associated with steroid responsive acute GI GVHD and an exhausted phenotype with steroid resistance. Future studies are needed to confirm the predictive value of specific gene expression profiles as biomarkers of corticosteroid response at diagnostic biopsy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Acute Gastrointestinal Toxicity Results from a Multi-Institution, Phase 2, Randomized Controlled Trial Comparing 3D-Conformal Radiotherapy (3DCRT) Versus Intensity Modulated Radiotherapy (IMRT) for Locally-Advanced Rectal Cancer (TRI-LARC).

<h3>Purpose/Objective(s)</h3> The primary aim of this trial was to compare the incidence of grade 2 or above acute gastrointestinal (GI) toxicity for patients undergoing 3DCRT versus IMRT in the preoperative setting for locally-advanced rectal cancer. Secondary objectives included quality of life and other acute and late toxicity. <h3>Materials/Methods</h3> The trial was designed to have 80% power to detect a difference between a hypothesized 37% acute toxicity rate in the 3DCRT arm (Bosset et al, 2006) and 20% in the IMRT arm, with a sample size of 120 per arm, and a 0.05 two-sided level of significance. Eligible participants were adults aged 18 or over scheduled to receive pre-operative pelvic chemo-radiotherapy for histologically-confirmed rectal adenocarcinoma. Exclusion criteria included prior pelvic radiotherapy, inflammatory bowel disease, hip replacements, and previous bowel surgery. Prescription dose was 50.4 Gray in 28 fractions over 5.5 weeks with concurrent 5-fluorouracil or capecitabine chemotherapy. Participants were centrally randomized 1:1 to receive 3DCRT or IMRT. Each individual radiotherapy volume and plan was reviewed centrally to ensure compliance with the trial's RTQA specifications. Toxicity was graded and reported according to CTCAE version 4.0 (National Institutes of Health National Cancer Institute). Acute toxicity was assessed weekly during radiotherapy, and at 2- and 4-weeks post-treatment. <h3>Results</h3> 94 patients were enrolled. 77% were male and median age was 59.4. Two participants from the 3DCRT arm did not complete radiotherapy as planned and were excluded from analysis. 25 (56%) of participants from the 3dCRT arm and 23 (49%) from the IMRT arm experienced acute grade 2 or above GI toxicity (p=.670). Rates for grade 3 GI toxicity were 8 (18%) and 5 (11%) for 3dCRT and IMRT, respectively (p=.494). Grade 3 GI events included diarrhea (n=11), nausea (n=2), intestinal obstruction (n=1), oral mucositis (n=1), and rectal pain (n=1). The study closed early due to absence of evidence of a difference between arms at the interim analysis. <h3>Conclusion</h3> No significant difference in rates of acute GI toxicity with IMRT versus 3DCRT for locally advanced rectal cancer was seen. Although IMRT can reduce dose to organs at risk, it appears to be similarly safe in terms of acute GI toxicity to deliver this treatment with 3DCRT.

A Glasgow-Blatchford Bleeding Score of >2 Is a Poor Predictor of Endoscopic Intervention in Nonvariceal Upper GI Bleeding.

Recent data show that a Glasgow-Blatchford Bleeding Score (GBS) >2 does not identify patients with upper gastrointestinal (GI) bleeding who benefit from inpatient esophagogastroduodenoscopy (EGD). This study aimed to determine the rate of endoscopic hemostatic interventions (HI) in patients with nonvariceal acute GI bleeding (NVAUGIB) admitted with a GBS >2. Secondary aims included comparison of clinical outcomes in patients with and without HI and cost of nontherapeutic EGDs. We conducted a retrospective review of medical records of patients admitted to a referral hospital for NVAUGIB from January 2015 to December 2017. Mortality, blood transfusion rates, length of stay, length of intensive care unit stay, and cost of a nontherapeutic EGD were outcomes of interest. Patients 18 years of age and older of both sexes were included. The accuracy of the GBS >2 cutoff was determined using receiver operating characteristic curve analysis. A total of 357 patients were included and only 58 (16.2%) required HI. The area under the curve for GBS >2 as a predictor of HI was 0.57. The performance of HI did not influence mortality (P = 0.33), blood transfusion rates (P = 0.51), length of stay (P = 0.2), or length of intensive care unit stay (P = 0.36). The estimated cost of performing nontherapeutic EGD was approximately $855,000 for the 299 patients who did not need HI. A GBS cutoff of >2 is not an accurate criterion to triage patients with NVAUGIB for inpatient emergent EGD. More clinically meaningful and cost-effective methods to triage these patients are necessary.

Anal squamous cell carcinoma: Impact of radiochemotherapy evolution over years and an explorative analysis of MRI prediction of tumor response in a mono-institutional series of 131 patients.

Radiochemotherapy (RCHT) for the treatment of anal squamous cell carcinoma (ASCC) has evolved dramatically, also thanks to intensity-modulated RT (IMRT) and 3D image guidance (3D IGRT). Despite most patients presenting fair outcomes, unmet needs still exist. Predictors of poor tumor response are lacking; acute toxicity remains challenging; and local relapse remains the main pattern of failure. Between 2010 and 2020, ASCC stages I-III treated with 3D conformal radiotherapy or IMRT and CDDP-5FU or Mytomicine-5FU CHT were identified. Image guidance accepted included 2D IGRT or 3D IGRT. The study endpoints included freedom from locoregional recurrence (FFLR), colostomy free survival (CFS), freedom from distant metastasis (FFDM), overall survival (OS), and acute and late toxicity as measured by common terminology criteria for adverse events (CTCAE) version 5.0. An exploratory analysis was performed to identify possible radiomic predictors of tumor response. Feature extraction and data analysis were performed in Python™, while other statistics were performed using SPSS® v.26.0 software (IBM®). A total of 131 patients were identified. After a median FU of 52 months, 83 patients (63.4%) were alive. A total of 35 patients (26.7%) experienced locoregional failure, while 31 patients (23.7%) relapsed with distant metastasis. Five year FFLR, CFS, DMFS and PS resulted 72.3%, 80.1%, 74.5% and 64.6%. In multivariate analysis, 2D IGRT was associated with poorer FFLR, OS, and CFS (HR 4.5, 4.1, and 5.6, respectively); 3DcRT was associated with poorer OS and CFS (HR 3.1 and 6.6, respectively). IMRT reduced severe acute gastro-intestinal (GI) and severe skin acute toxicity in comparison with 3DcRT. In the exploratory analysis, the risk of relapse depended on a combination of three parameters: Total Energy, Gray Level Size Zone Matrix's Large Area High Gray Level Emphasis (GLSZM's LAHGLE), and GTV volume. Advances in radiotherapy have independently improved the prognosis of ASCC patients over years while decreasing acute GI and skin toxicity. IMRT and daily 3D image guidance may be considered standard of care in the management of ASCC. A combination of three pre-treatment MRI parameters such as low signal intensity (SI), high GLSZM's LAHGLE, and GTV volume could be integrated in risk stratification to identify candidates for RT dose-escalation to be enrolled in clinical trials.

Treatment Outcomes of Postoperative Ultra-Hypofractionated Stereotactic Body Radiotherapy in Prostate Cancer

<h3>Purpose/Objective(s)</h3> Prospective randomized phase 3 trials have shown that hypofractionated radiotherapy (RT) regimens are safe and effective for definitive prostate RT. There is, however, a scarcity of data describing the outcomes of ultra-hypofractionation in the postoperative setting. The purpose of this study was to assess the safety of ultra-hypofractionated RT to prostate bed using stereotactic body RT (SBRT) technique. <h3>Materials/Methods</h3> The clinical data of 69 prostate cancer patients who received postoperative prostate bed SBRT between August 2018 and September 2020 were reviewed retrospectively. All patients had had radical prostatectomy, and 44 (63.8%) had pelvic lymph node dissection, with a median of 14 (range: 2–34) lymph nodes dissected. The primary endpoints were failure from biochemical failure (FFBF) and acute and late gastrointestinal (GI) and genitourinary (GU) toxicities. Secondary endpoint was progression free survival (PFS). <h3>Results</h3> The median age was 64 years (range: 43–76 years). Thirty patients (43.5%) received adjuvant RT and 39 (56.5%) had salvage RT median 12.4 months (range: 1.5–137.6 months) after surgery. Median SBRT fraction and total doses were 7 Gy (range: 6–7.3 Gy) and 30 Gy (30–36.5 Gy), respectively delivered in 5 days. Majority of patients (82.7%) had high risk disease and only 13 patients (18.8%) had lymph node metastasis. Seminal vesicle invasion was observed in 22 patients (31.9%) and 49 patients (71%) had extracapsular invasion. Forty-eight patients (69.6%) had positive surgical margin. Pre-SBRT and post-SBRT PSA values were 0.37 ng/mL and 0.05 ng/mL, respectively. 27 patients (39.1%) also received adjuvant androgen deprivation therapy (ADT) after SBRT and post-treatment PSA nadir value was 0.01 ng/mL. Median follow-up time was 23.8 months (range: 2.8–37.2 months). The 2-year FFBF and PFS were 91.4% and 87%, respectively. Seven patients (10.1%) had BF median 18.5 months (range: 1.7–33.5 months) after completion of SBRT. Disease progression was observed in 10 patients (14.5%) median 13.9 months after treatment. Acute GI and GU system toxicities of grade 2 or greater were observed in 13% and 14.5% of patients, respectively. Late GI and GU toxicities of grade 2 or greater were observed in 4.3% and 16% of patients, respectively. <h3>Conclusion</h3> SBRT delivered to the prostate bed over a 5-day period was found to be safe, with acceptable acute and late toxicities. Longer follow-up and randomized trials with a large patient population, however, are required to validate our findings.

The Impact of Image Guided Radiation Therapy (IGRT) on Efficacy and Toxicity of Prostate Cancer: A Systematic Review and Meta-Analysis

<h3>Purpose/Objective(s)</h3> Image-guided radiation therapy (IGRT) is widely used to correct prostate localization, but there have been no consistent conclusions regarding the effect of IGRT on the toxicity and survival in the absence of level 1 evidence. The purpose of this study is to perform a systematic review and meta-analysis of efficacy and toxicity of IGRT in prostate cancer. <h3>Materials/Methods</h3> A systematic review, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guide-lines, was conducted using PubMed, Embase, Medline databases and Cochrane Library databases until February 2022. Two investigators independently searched and selected literature, including randomized controlled trials (RCTs) and cohort studies (CRS). The data on efficacy and toxicity were extracted for quality assessment and meta-analysis to quantify the effect of IGRT on prostate-specific antigen (PSA) relapse-free survival, biochemical failure-free survival (BFFS), overall survival (OS), gastrointestinal (GI) toxicity and genitourinary (GU) toxicity. Heterogeneity assessment was performed using the <i>χ</i>² test and the <i>I</i>² statistic. Significant heterogeneity was indicated by <i>P</i> <0.05 in Cochrane Q tests and a ratio greater than 50% in <i>I</i>² statistics, which led to the use of random-effects models according to the DerSimonian and Laird method. <h3>Results</h3> The initial search strategy identified 2816 records in total, and 19 studies with 5186 patients met inclusion criteria after removing duplicates, screening, and full article review for the final meta-analysis. The results revealed that IGRT significantly reduced not only the grade 2 (G2) or worse (G2+) acute GI toxicity (risk ratio [RR] = 0.55 [95% confidence interval (CI), 0.36-0.85]; <i>P</i> = 0.007) and GU toxicity (RR = 0.82 [95% CI, 0.72-0.95]; <i>P</i> = 0.006), but also the G2+ late GI toxicity (hazard ratio [HR] = 0.25 [95% CI, 0.07-0.87]; <i>P</i> = 0.03) compared with non-IGRT. Moreover, IGRT significantly improved PSA relapse-free survival (HR = 0.43 [95% CI, 0.20-0.92]; <i>P</i> = 0.03). However, it was found that high frequency (once daily) IGRT took no advantage in BFFS (HR = 0.68 [95% CI, 0.41-1.12]; <i>P</i> = 0.13) and OS (HR = 1.34 [95% CI, 0.60-2.99]; <i>P</i> = 0.47) in prostate cancer than low frequency (once weekly or less) IGRT. <h3>Conclusion</h3> This is the first meta-analysis to demonstrate that IGTR control in prostate cancer significantly reduces G2+ acute GI and GU toxicity and improves PSA relapse-free survival. While it is important not to underestimate the negative effects on high frequency IGRT, which has little benefit on BFFS and OS.

Determining Combined Modality Dosimetric Constraints by Integration of IMRT and LDR Prostate Brachytherapy Dosimetry

Determining Combined Modality Dosimetric Constraints by Integration of IMRT and LDR Prostate Brachytherapy Dosimetry <h3>Purpose/Objective(s)</h3> Combined external beam radiation therapy (EBRT) and prostate brachytherapy is one standard of care for men with prostate cancer. Dosimetric correlation of organ at risk (OAR) has been limited by the lack of spatial registration and differences in biological effectiveness between EBRT and brachytherapy dose. This study utilized a validated technique to spatially combine three-dimensional biological effective dose (BED) distributions from different modalities to more accurately depict a composite dose. We use this technique to correlate dosimetry with genitourinary (GU) and gastrointestinal (GI) toxicity in an effort to propose conservative dosimetric tolerances for OARs during combination therapy for prostate cancer. <h3>Materials/Methods</h3> The study cohort consisted of 144 intermediate and high-risk prostate cancer patients treated with combination therapy. Patients received 45 Gy using IMRT, either by static field or modulated arc, and 100 Gy using ¹⁰³Pd. Dosimetry was converted voxel-by-voxel to BED and combined using deformable image or inherent DICOM registration. Acute and late GU and GI toxicity was scored using CTCAE and correlated with combined BED. Biological effective doses for each toxicity group were compared using analysis of variance (α=0.05). <h3>Results</h3> Using dose methodology, the mean prostate BED was 223.5 ± 24.2 Gy. Mean urethral dose and D10 were 182.5 ± 22.8 and 232.0 ± 37.0 respectively. Mean rectal dose and D2cc were 33.2 ± 7.9 and 86.4 ± 24.4 respectively. CTCAE toxicity is reported in Table 1. Overall, there was minimal grade 3+ toxicity. No statistical differences were noted among any of the toxicity grades and there was no correlation between urethral or rectal dose and toxicity. <h3>Conclusion</h3> This study demonstrates the feasibility of using the spatial combination of biologic effective doses for OARs in combination EBRT and brachytherapy for prostate cancer. In this study cohort, the level of toxicity was generally less than reported elsewhere. This dataset serves as an opportunity to propose using combined constraints as a conservative estimate for future studies to estimate OAR tolerances. Initially, we propose conservative combination constraints equal to one standard deviation below our mean patient dosimetry: Urethra D10 < 160 Gy and Rectum D2cc < 60 Gy. The process of establishing a useful BED between two different treatments can help redefine OAR tolerances and has applicability for other treatment sites with combined therapy such as cervix cancer and re-irradiation.

Dosimetric Predictors of Acute and Late Gastrointestinal Toxicities in Stereotactic Online Adaptive Magnetic Resonance-Guided Radiotherapy (SMART) for Locally Advanced Pancreatic Adenocarcinoma

<h3>Purpose/Objective(s)</h3> Ablative SBRT is growing in use for non-metastatic pancreatic adenocarcinoma (PAC). Data for organ-at-risk (OAR) constraints have been historically limited by the inability to account for inter-fraction changes in OAR positions and their potential effects on toxicity risk. The purpose of this single institution, retrospective study was to investigate the relationships of dose and volume to OAR during daily stereotactic, MRI-guided online adaptive radiotherapy (SMART). We hypothesized that the daily, dose-volume data for OARs generated through the process of daily adaptation could be leveraged to identify dosimetric drivers of gastrointestinal (GI) toxicities for pancreas SBRT. <h3>Materials/Methods</h3> 147 patients with PAC were treated with five-fraction SMART on a 0.35 MR Linac at our institution from July 2018 to August 2021. All patients met clinical OAR constraints, typically V36Gy <0.5cc to OAR. Patients were reviewed and evaluated using the common terminology criteria for adverse events (CTCAE) V5.0 for possibly, probably, or definitely related to radiation acute (≤3 months) and late (>3 months) toxicities and confirmed by an attending GI radiation oncologist. Each OAR: stomach, duodenum, and small bowel (SB) was matched to a ≥ grade 2 (Gr2+) toxicity endpoint composite group. Due to the high degree of multicollinearity between dose-volumes within OARs, a least absolute shrinkage selector operator (LASSO) regression model was constructed using R 4.1.2 for each. The models were grouped by V15Gy, V20Gy, V25Gy, V30Gy, V33Gy, and V36Gy to OARs. Following identification of dose levels (Gy) associated with each toxicity group, receiver operator curve (ROC) analysis was performed for the combined average SB and duodenum V33Gy across all fractions to identify critical volumes at those dose levels most predictive of risk. <h3>Results</h3> 18 of 147 patients experienced ≥1 Gr2+ acute or late GI toxicity. 17 had duodenal toxicities, including 10 Gr2, 6 Gr3, and 1 Gr4 (duodenal ulcer). Acute Gr2+ occurred in 8.84% of patients. Of the 7 Gr3+ duodenal toxicities, 71% were duodenal ulcers. The most significant predictor of Gr 2+ duodenal and SB toxicity was V33Gy odds ratio of 1.65 (95% CI 1.05-2.72) and 1.60 (95% CI 1.01-2.54) per cc of OAR, respectively. On ROC analyses for duodenum and SB, AUC was 0.72 for each. For duodenum, the optimal cut-point was 1cc, with true positive (TP) and true negative (TN) rates of 17.8% of 94.9% above that volume. For SB, it was 1.75cc (TP: 16.7%; TN: 94.3%). A specific stomach dose that related to toxicities was not identified. <h3>Conclusion</h3> After SMART, the dose-volume threshold of V33Gy was associated with Gr2+ acute and late toxicities for the duodenum and SB. These data provide an evidence-based understanding of dose-constraints to OAR for PAC and are the first to our knowledge to account for inter-fraction motion using daily volumetric on-board MRI. These metrics can be utilized to guide future dose-volume choices for patients undergoing SMART or non-adaptive SBRT.

S3393 Diffuse Large B Cell Lymphoma Presenting as Bleeding and Hypoalbuminemia: A Case Report

Introduction: Diffuse large B cell lymphoma (DLBCL) accounts for 38-57% of primary gastrointestinal (GI) lymphomas. Initial presentation can include nonspecific symptoms, such as weight loss, fatigue, and nausea. Imaging studies are typically nonspecific as well. Therefore, patients are commonly misdiagnosed or diagnosis is delayed. 20-30% of GI lymphomas are in the small intestine but are rarely in the jejunum. We present a rare case of jejunal DLBCL and illustrate the diagnostic difficulties. Case Description/Methods: A 49-year-old male presented with weeks of dizziness, dyspnea, hematochezia, and 30-pound unintentional weight loss over 4 months. Labs were notable for anemia and severe hypoalbuminemia (1.9 g/dL). Esophagogastroduodenoscopy and colonoscopy revealed diverticulosis and hemorrhoids, which were the presumed etiology of his symptoms. One month later, the patient presented similarly. Imaging demonstrated bilateral pulmonary emboli and intramural thickening of the jejunum. For worsening hypoalbuminemia (1.3 g/dL), the patient was scheduled for outpatient work-up. However, he presented again for acute GI bleed and severe anemia. Push enteroscopy revealed patchy mucosal changes in the jejunum and biopsies were consistent with DLBCL. The patient was started on chemotherapy and reported improvement in symptoms and resolution of his GI bleed. Discussion: Primary GI DLBCL is rarely found in the jejunum due to the lack of lymphoid tissue, making this case noteworthy. GI DLBCL is difficult to diagnose, since patients may be asymptomatic or present with nonspecific symptoms. Small intestinal DLBCL can present with GI bleeding, which can easily lead to a misdiagnosis of a diverticular or hemorrhoidal bleed. Imaging studies can be nonspecific and obtaining confirmation through biopsy can prove difficult due to its location, further complicating the diagnosis. One unique aspect of this case that led to the diagnosis was the severity of hypoalbuminemia. The patient was not malnourished, had no clinically apparent protein-losing enteropathy, and no proteinuria or liver failure, making underlying malignancy likely. Differential diagnoses of small bowel wall thickening on imaging is wide and includes infections, primary inflammatory processes such as IBD, and neoplastic lesions. DLBCL may have unusual clinical presentations, subtle laboratory findings and may not be easily diagnosed with initial imaging; thus, clinicians should remain vigilant of this possible diagnosis.