RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis.

Upon ligand binding, RIPK1 is recruited to tumor necrosis factor receptor superfamily (TNFRSF) and Toll-like receptor (TLR) complexes promoting prosurvival and inflammatory signaling. RIPK1 also directly regulates caspase-8-mediated apoptosis or, if caspase-8 activity is blocked, RIPK3-MLKL-dependent necroptosis. We show that C57BL/6 Ripk1(-/-) mice die at birth of systemic inflammation that was not transferable by the hematopoietic compartment. However, Ripk1(-/-) progenitors failed to engraft lethally irradiated hosts properly. Blocking TNF reversed this defect in emergency hematopoiesis but, surprisingly, Tnfr1 deficiency did not prevent inflammation in Ripk1(-/-) neonates. Deletion of Ripk3 or Mlkl, but not Casp8, prevented extracellular release of the necroptotic DAMP, IL-33, and reduced Myd88-dependent inflammation. Reduced inflammation in the Ripk1(-/-)Ripk3(-/-), Ripk1(-/-)Mlkl(-/-), and Ripk1(-/-)Myd88(-/-) mice prevented neonatal lethality, but only Ripk1(-/-)Ripk3(-/-)Casp8(-/-) mice survived past weaning. These results reveal a key function for RIPK1 in inhibiting necroptosis and, thereby, a role in limiting, not only promoting, inflammation.

Evaluating the effectiveness of community health worker interventions on glycaemic control in type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Interventions with community health workers, trained to provide basic medical education and holistic support, have been used to enhance type 2 diabetes outcomes in various settings. Evidence of their effectiveness is poor because of variations in intervention design and duration. We did a systematic review of randomised trials evaluating the effectiveness of community health worker interventions integrated into conventional care to improve glycaemic control in adults with diabetes. METHODS: In this systematic review and meta-analysis, we included randomised trials of community health worker interventions of at least-12 months' duration in adults with type 2 diabetes that compared HbA1c levels with usual care. We searched Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, CINAHL and the Web of Science Core Collection for studies published in English between Jan 1, 2000, and March 1, 2023, for studies containing "community health worker" or "lay health worker", and "type 2 diabetes". We extracted both qualitative and quantitative data to assimilate community health worker intervention characteristics. We did a meta-analysis comparing changes in HbA1c levels from baseline between intervention groups and usual care groups. To be included in the meta-analysis, studies had to have HbA1c values at baseline and after 12 months and a patient dropout rate of less than 25% at 12 months follow-up. The main outcome was the mean weighted difference of % change in HbA1c after at least 12 months, assessed using Revman, the inverse variance-weighted average model (IVW). Quality was assessed using the Cochrane Rob2 tool. FINDINGS: Seven of 86 retrieved studies were eligible for inclusion; six studies were conducted in the USA and one study in Indigenous Australia. Participants in all studies were recruited from Latino, African American and Indigenous Australian ethnic minority groups. The meta-analysis of six studies including 1280 participants (mean age 52·6 years [SD 3·68]; 832 [65%] female and 448 [35%] male) showed a significant improvement in HbA1c level at 12 months follow-up, with a mean weighted difference of 0·5% (95% CI 0·31-0·68) in the community health worker intervention group (p<0·0001), that reached the generally accepted minimal clinically important difference (≥0·5%). Outcome heterogeneity was low. INTERPRETATION: Community health worker interventions showed a significant reduction in HbA1c level adjunct to usual care, but caution must be taken given the point effect estimate is only just the MCID, and the true effect could be smaller. Given the current resource constraints faced by primary care, community health worker interventions could be innovative in informing the primary and secondary management of diabetes care in UK practice. A cost-effectiveness analysis of these interventions is required before implementation in routine diabetes care can be recommended. FUNDING: None.

Inclusion of Positive Self-reporting by Mothers of Substance Exposed Neonates Increases the Predictability of NAS Severity Over Toxicology Alone.

OBJECTIVES: The rise in opioid use among pregnant women has resulted in an increase in the incidence of neonatal abstinence syndrome (NAS). Despite the focus on opioid use, prenatal polysubstance exposure is often associated with NAS diagnosis and severity. Drug toxicology screens such as urine drug screens and umbilical cord toxicology are dependent upon the substance, timing, frequency, and dose to detect substances present and can underestimate the neonatal exposure. The aim of this study was to identify the predictability of the consequences of prenatal polysubstance exposure versus opioid only exposure based on toxicology and toxicology plus self-report. METHODS: Neonates > 35 weeks gestation with prenatal opioid exposure were included in this retrospective data analysis. NAS was identified using maternal urine drug screen (UDS) toxicology, self-reported exposure during pregnancy, and neonatal toxicology. Analysis was conducted using Stata 15.1 utilizing McNemar's test, chi-square for categorical outcomes, and Wilcoxon test for numerical outcomes. RESULTS: A statistically significant difference in length of stay and length of treatment with poly-exposed neonates was observed when maternal self-report was considered with toxicology, but not with toxicology alone. This trend was observed for cumulative hospital length of stay as well as length and dose of treatment. CONCLUSIONS FOR PRACTICE: The findings in this report demonstrate that self-report is important for identifying substance of exposure. Three substances in particular that often require a change in treatment paradigm went undetected by toxicology were Gabapentin (20.9% of the population), Heroin (20.5% of the population), and Benzodiazepines (8.5% of the population). A healthy rapport with patients is often critical to effective clinical practice. Women with substance use disorder anticipate negative reactions from healthcare providers. Empathetic interview techniques to facilitate accurate disclosure may be more important to the treatment of the exposed neonate.

An Atypical Withdrawal Syndrome in Neonates Prenatally Exposed to Gabapentin and Opioids.

We report a retrospective case series of 19 infants exposed to both opioids and gabapentin prenatally. We describe a unique behavioral phenotype in 15 of these infants and report a treatment strategy.

Genome-wide associations with flowering time in switchgrass using exome-capture sequencing data.

Flowering time is a major determinant of biomass yield in switchgrass (Panicum virgatum), a perennial bioenergy crop, because later flowering allows for an extended period of vegetative growth and increased biomass production. A better understanding of the genetic regulation of flowering time in switchgrass will aid the development of switchgrass varieties with increased biomass yields, particularly at northern latitudes, where late-flowering but southern-adapted varieties have high winter mortality. We use genotypes derived from recently published exome-capture sequencing, which mitigates challenges related to the large, highly repetitive and polyploid switchgrass genome, to perform genome-wide association studies (GWAS) using flowering time data from a switchgrass association panel in an effort to characterize the genetic architecture and genes underlying flowering time regulation in switchgrass. We identify associations with flowering time at multiple loci, including in a homolog of FLOWERING LOCUS T and in a locus containing TIMELESS, a homolog of a key circadian regulator in animals. Our results suggest that flowering time variation in switchgrass is due to variation at many positions across the genome. The relationship of flowering time and geographic origin indicates likely roles for genes in the photoperiod and autonomous pathways in generating switchgrass flowering time variation.

Beneficial effects of natural eggshell membrane (NEM) on multiple indices of arthritis in collagen-induced arthritic rats.

OBJECTIVES: This study was performed to evaluate the potential efficacy of natural eggshell membrane (NEM) in collagen-induced arthritic rats, a well-established rodent model of inflammation and rheumatoid arthritis. METHODS: Rats with developing type II collagen-induced arthritis (CIA) were treated once daily by oral gavage on study days -14 to 17 with vehicle or NEM (52 mg/kg body weight). Rats were euthanized on study day 17. Efficacy was assessed by daily ankle caliper measurements, ankle diameter expressed as area under the curve (AUCd0-17), and histopathologic evaluation of ankles and knees. Serum biomarkers of cartilage function and inflammation [collagen type II C-telopeptide (CTXII), cartilage oligomeric matrix protein (COMP), and alpha-2-macroglobulin (A2M)] were measured by ELISA. RESULTS: Treatment with NEM resulted in significant beneficial effects on the daily ankle diameter measurements and ankle diameter AUC. Ankle and knee histopathology scores were significantly reduced (36% and 43% reduction of summed individual histopathology scores for ankle and knee, respectively; p < 0.05) toward normal for rats given NEM compared to vehicle controls. The percent reduction of serum CTXII, COMP, and A2M in NEM-treated rats ranged from 30% to 72% (p < 0.05). CONCLUSIONS: NEM significantly improved multiple aspects of inflammatory arthritis including inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation. This study provides further support for the use of CTXII, COMP, and A2M as relevant biomarkers that were responsive to NEM.

Diversity and population structure of northern switchgrass as revealed through exome capture sequencing.

Panicum virgatum L. (switchgrass) is a polyploid, perennial grass species that is native to North America, and is being developed as a future biofuel feedstock crop. Switchgrass is present primarily in two ecotypes: a northern upland ecotype, composed of tetraploid and octoploid accessions, and a southern lowland ecotype, composed of primarily tetraploid accessions. We employed high-coverage exome capture sequencing (~2.4 Tb) to genotype 537 individuals from 45 upland and 21 lowland populations. From these data, we identified ~27 million single-nucleotide polymorphisms (SNPs), of which 1 590 653 high-confidence SNPs were used in downstream analyses of diversity within and between the populations. From the 66 populations, we identified five primary population groups within the upland and lowland ecotypes, a result that was further supported through genetic distance analysis. We identified conserved, ecotype-restricted, non-synonymous SNPs that are predicted to affect the protein function of CONSTANS (CO) and EARLY HEADING DATE 1 (EHD1), key genes involved in flowering, which may contribute to the phenotypic differences between the two ecotypes. We also identified, relative to the near-reference Kanlow population, 17 228 genes present in more copies than in the reference genome (up-CNVs), 112 630 genes present in fewer copies than in the reference genome (down-CNVs) and 14 430 presence/absence variants (PAVs), affecting a total of 9979 genes, including two upland-specific CNV clusters. In total, 45 719 genes were affected by an SNP, CNV, or PAV across the panel, providing a firm foundation to identify functional variation associated with phenotypic traits of interest for biofuel feedstock production.

The Munroe-Meyer Approach: Continuous Integration of Didactic Instruction, Research, and Clinical Practice.

Increased demand for applied behavior analysis (ABA) services has increased the need for additional masters-level practitioners and doctoral-level academicians and clinical directors. Based on these needs, the University of Nebraska Medical Center's (UNMC) Munroe-Meyer Institute has developed a PhD program. The academic structure at UNMC allowed us to create our PhD program in a relatively quick and efficient manner. Our PhD program has many unique features, including (a) close integration of didactic instruction with clinical and research training provided by leading experts in ABA in which students immediately apply concepts introduced in the classroom during coordinated clinical and research practica; (b) structured grant writing training in which students learn to write and submit an NIH-level grant;

Nucleotide polymorphism and copy number variant detection using exome capture and next-generation sequencing in the polyploid grass Panicum virgatum.

Switchgrass (Panicum virgatum) is a polyploid, outcrossing grass species native to North America and has recently been recognized as a potential biofuel feedstock crop. Significant phenotypic variation including ploidy is present across the two primary ecotypes of switchgrass, referred to as upland and lowland switchgrass. The tetraploid switchgrass genome is approximately 1400 Mbp, split between two subgenomes, with significant repetitive sequence content limiting the efficiency of re-sequencing approaches for determining genome diversity. To characterize genetic diversity in upland and lowland switchgrass as a first step in linking genotype to phenotype, we designed an exome capture probe set based on transcript assemblies that represent approximately 50 Mb of annotated switchgrass exome sequences. We then evaluated and optimized the probe set using solid phase comparative genome hybridization and liquid phase exome capture followed by next-generation sequencing. Using the optimized probe set, we assessed variation in the exomes of eight switchgrass genotypes representing tetraploid lowland and octoploid upland cultivars to benchmark our exome capture probe set design. We identified ample variation in the switchgrass genome including 1,395,501 single nucleotide polymorphisms (SNPs), 8173 putative copy number variants and 3336 presence/absence variants. While the majority of the SNPs (84%) detected was bi-allelic, a substantial number was tri-allelic with limited occurrence of tetra-allelic polymorphisms consistent with the heterozygous and polyploid nature of the switchgrass genome. Collectively, these data demonstrate the efficacy of exome capture for discovery of genome variation in a polyploid species with a large, repetitive and heterozygous genome.

Two-dimensionality of yeast colony expansion accompanied by pattern formation.

Yeasts can form multicellular patterns as they expand on agar plates, a phenotype that requires a functional copy of the FLO11 gene. Although the biochemical and molecular requirements for such patterns have been examined, the mechanisms underlying their formation are not entirely clear. Here we develop quantitative methods to accurately characterize the size, shape, and surface patterns of yeast colonies for various combinations of agar and sugar concentrations. We combine these measurements with mathematical and physical models and find that FLO11 gene constrains cells to grow near the agar surface, causing the formation of larger and more irregular colonies that undergo hierarchical wrinkling. Head-to-head competition assays on agar plates indicate that two-dimensional constraint on the expansion of FLO11 wild type (FLO11) cells confers a fitness advantage over FLO11 knockout (flo11Δ) cells on the agar surface.

Insulin autoimmune syndrome (Hirata Disease) in European Caucasians taking α-lipoic acid.

OBJECTIVE: Lipoic acid (LA) is a widely used nutritional supplement and is sometimes used as an adjuvant treatment for diabetic neuropathy and other conditions. Insulin autoimmune syndrome (IAS, Hirata disease) is a rare cause of spontaneous hypoglycaemia, extremely high serum insulin levels and high titres of autoantibodies against endogenous insulin despite no prior exposure to exogenous insulin. In Japanese individuals, IAS is associated with the human leucocyte antigen (HLA) HLA-DRB1*04:06 allele and often occurs upon exposure to sulphhydryl-containing compounds including LA. Only one case has been reported in Caucasians. We now report six Caucasian patients taking LA with IAS and describe a unique HLA subtype in these patients. RESEARCH DESIGN AND METHODS: Six Caucasian patients (M = 3; F = 3), median age 63 years, presented with spontaneous episodes of fasting and postabsorptive hypoglycaemia associated with mainly neuroglycopenic symptoms. No patient was treated with insulin or had an insulinoma. Hypoglycaemic symptoms appeared 30 and 120 days after taking lipoic acid (LA; 600 mg/day). Case histories and standard laboratory analyses were utilized. RESULTS: Discontinuation of LA resulted in a reduction in hypoglycaemic episodes. All patients were treated with oral or iv glucose and prednisone (12.5-25 mg/day). HLA analysis revealed the HLA-DRB1*04:03 allele in five patients, while the HLA-DRB1*04:06 allele was present in one patient. CONCLUSIONS: This is the first report of LA-related IAS in Caucasians who possess the HLA-DRB1*04:03 allele, implicating this allele in the genetic susceptibility to IAS in Caucasians. The greater occurrence of the HLA-DRB1*04:03 allele in Caucasian and other populations, combined with the growing use of LA in developed countries, may be a future predictor of additional cases of IAS.

PET/CT-Based Absorbed Dose Maps in 90Y Selective Internal Radiation Therapy Correlate with Spatial Changes in Liver Function Derived from Dynamic MRI.

Functional liver parenchyma can be damaged from treatment of liver malignancies with 90Y selective internal radiation therapy (SIRT). Evaluating functional parenchymal changes and developing an absorbed dose (AD)-toxicity model can assist the clinical management of patients receiving SIRT. We aimed to determine whether there is a correlation between 90Y PET AD voxel maps and spatial changes in the nontumoral liver (NTL) function derived from dynamic gadoxetic acid-enhanced MRI before and after SIRT. Methods: Dynamic gadoxetic acid-enhanced MRI scans were acquired before and after treatment for 11 patients undergoing 90Y SIRT. Gadoxetic acid uptake rate (k1) maps that directly quantify spatial liver parenchymal function were generated from MRI data. Voxel-based AD maps, derived from the 90Y PET/CT scans, were binned according to AD. Pre- and post-SIRT k1 maps were coregistered to the AD map. Absolute and percentage k1 loss in each bin was calculated as a measure of loss of liver function, and Spearman correlation coefficients between k1 loss and AD were evaluated for each patient. Average k1 loss over the patients was fit to a 3-parameter logistic function based on AD. Patients were further stratified into subgroups based on lesion type, baseline albumin-bilirubin scores and alanine transaminase levels, dose-volume effect, and number of SIRT treatments. Results: Significant positive correlations (ρ = 0.53-0.99, P < 0.001) between both absolute and percentage k1 loss and AD were observed in most patients (8/11). The average k1 loss over 9 patients also exhibited a significant strong correlation with AD (ρ ≥ 0.92, P < 0.001). The average percentage k1 loss of patients across AD bins was 28%, with a logistic function model demonstrating about a 25% k1 loss at about 100 Gy. Analysis between patient subgroups demonstrated that k1 loss was greater among patients with hepatocellular carcinoma, higher alanine transaminase levels, larger fractional volumes of NTL receiving an AD of 70 Gy or more, and sequential SIRT treatments. Conclusion: Novel application of multimodality imaging demonstrated a correlation between 90Y SIRT AD and spatial functional liver parenchymal degradation, indicating that a higher AD is associated with a larger loss of local hepatocyte function. With the developed response models, PET-derived AD maps can potentially be used prospectively to identify localized damage in liver and to enhance treatment strategies.

Follow-up for human papillomavirus-related oropharynx cancer concentrated on unequal symptom change (FOCUS): Prospective patient-reported outcome collection.

BACKGROUND: Post-treatment surveillance recommendations for oropharyngeal cancer do not vary with p16 status despite the differences in outcomes. The optimal algorithm personalizing follow-up for these patients remains undefined. Here, we evaluate the feasibility and utility of incorporating electronic patient-reported outcomes (ePROs) and circulating tumor DNA (ctDNA) into routine surveillance for patients treated for p16+ oropharynx cancer. METHODS: A prospective registry was developed in which ePROs and ctDNA were incorporated into routine surveillance among patients with oropharynx cancer. ePROs were emailed monthly for 1 year and blood HPV ctDNA testing was performed every 3-6 months. The primary objective was to assess patient compliance with ePRO-based surveillance with adequate compliance defined as ≥85% of patients completing monthly ePROs. Sensitivity, specificity, and positive/negative predictive values to detect recurrence were calculated for ePROs, HPV ctDNA, or the combination. RESULTS: Of 122 patients who initially expressed interest, 76 completed the electronic consent process and 44/76 (58%) were compliant with monthly surveys over 1 year; thus adequate compliance was not achieved. Technical difficulties associated with ePRO receipt through email largely limited participation. Provider feedback was significantly associated with heightened ePRO compliance. One hundred and six patients had ctDNA testing with a mean number of three tests per patient. Sensitivity to detect recurrence was 75% for the combination of ePROs and ctDNA. CONCLUSION: Despite lower than anticipated compliance with ePROs, our findings show promise for incorporation of HPV ctDNA into surveillance paradigms for HPV-related oropharynx cancer with suggestions of methods to optimize ePRO formats for personalized surveillance.

Impact of Epic Smartlist and Lumens Software in Improving OP-29 Compliance at a Tertiary Health Care Network.

Background OP-29 is a Centers for Medicaid and Medicare Services (CMS) measure to ensure that endoscopists recommend appropriate follow-up intervals after normal colonoscopy in average risk patients. Failure to report OP-29 compliance can adversely affect hospital quality star rating as well as reimbursement for health care. The aim of our quality improvement project was to improve OP-29 compliance to the top decile over three years. Methodology Our sample included patients between 50-75 years of age who received average risk screening colonoscopies with normal findings. We provided intensive education to endoscopists about the importance of OP-29 compliance, developed an Epic Smartlist that directs our endoscopists to list an appropriate reason for colonoscopy intervals other than 10 years, and monitored OP-29 compliance monthly. We became the first health network in the United States to implement the Lumens endoscopy report writing software (Epic Systems Corporation, Verona, USA) and added the OP-29-related Epic Smartlist to the Lumens colonoscopy note template. All statistical analyses were conducted in SPSS version 26 (IBM Corp., Armonk, USA) to compute the means and frequencies of outcomes. Results Our sample included 2,171 patients with a mean age of 60.5 years of whom the majority were female (57.2%) and Caucasians (90%). Our OP-29 score increased from 87.47% to 100% over the course of three years, and this steady improvement was seen broadly across our network. We compared our network score averages to our state and national averages and consistently demonstrated higher compliance rates while reaching the top decile by 2020. Conclusion We believe our improved OP-29 compliance has reduced colonoscopy overutilization, improved health care quality, and reduced health care costs for our patients and health network. To our knowledge, this is the first reported project towards improving OP-29 compliance utilizing the Epic Lumens software. Epic Lumens (Epic Systems Corporation, Verona, USA) added this Smartlist as quick buttons in the standard colonoscopy procedure note templates they built for other organizations to improve health care quality and cost nationally.

Comparative membrane incorporation of omega-3 fish oil triglyceride preparations differing by degree of re-esterification: A sixteen-week randomized intervention trial.

BACKGROUND: Fish oil is routinely concentrated into unmodified triglycerides, or trans-esterified into an ethyl ester form. Re-esterification of the ethyl ester form yields re-esterified triglycerides (rTG), which are reportedly more bioavailable than ethyl ester forms. However, the fidelity of the re-esterification process may yield variable triglyceride forms, with only 55-60% being rTG. OBJECTIVE: To determine whether the blood lipidomic response to supplementation with two rTG supplements, varying by degree of re-esterification, would differ between treatments. DESIGN: This was a double-blind, parallel-design, single-center, 128-day study with sixty young, healthy subjects randomized into two groups. One group received a >95% rTG (Ultimate Omega®), as 1,000 mg capsules containing 325 mg eicosapentaenoic acid (EPA) and 225 mg docosahexaenoic acid (DHA), and the other received a <70% rTG (MEG-3) as 1,000 mg capsules containing 300 mg EPA and 200 mg DHA. Total intake was 2,750 and 2,500 mg EPA+DHA for the Ultimate Omega® and MEG-3 groups, respectively, with blood drawn at 4, 16 and 24 weeks and analyzed for serum and erythrocyte phospholipid fatty acid (PLFA) content. RESULTS: For erythrocyte PLFA profiles, EPA, docosapentaenoic acid (DPA) and DHA percentage of total erythrocyte PLFA were significantly greater for the Ultimate Omega® group than for the MEG-3 group, at week 16 (P < 0.05), as were the EPA:arachidonic acid (AA) ratio, DHA:AA ratio and EPA+DHA:AA ratio. For serum PLFA profiles, increases in EPA:AA ratio and EPA+DHA:AA ratio were significantly greater at week 4 in the Ultimate Omega® group compared to the MEG-3 group (P < 0.05). CONCLUSIONS: These data suggest that the percentage of rTG in rTG fish oil preparations may evolve as a new chemoprofile/quality control marker that can influence its lipidomic pharmacodynamics. Additional investigations to assess the physiologic/vascular and metabolic/inflammasome responses to concentrated fish oil preparations differing in the percentage of rTG are warranted.

Is Apparent Diffusion Coefficient Established as an Imaging Biomarker for Stereotactic Body Radiation Therapy Assessment in Hepatocellular Carcinoma?

ABSTRACT: In this article, as part of this special issue on biomarkers of early response, we review currently available reports regarding magnetic resonance imaging apparent diffusion coefficient (ADC) changes in hepatocellular carcinoma (HCC) in response to stereotactic body radiation therapy. We compare diffusion image acquisition, ADC analysis, methods for HCC response assessment, and statistical methods for prediction of local tumor progression by ADC metrics. We discuss the pros and cons of these studies. Following detailed analyses of existing investigations, we cannot conclude that ADC is established as an imaging biomarker for stereotactic body radiation therapy assessment in HCC.

Predictors of Acute and Late Toxicity in Patients Receiving Chemoradiation for Unresectable Pancreatic Cancer.

Purpose: Patients with pancreatic cancer undergoing chemoradiation therapy may experience acute and chronic side effects. We conducted an exploratory analysis of patients with locally advanced pancreatic cancer (LAPC) undergoing definitive chemoradiation to identify factors influencing the occurrence of gastrointestinal (GI) bleeding, short-term radiation side effects, patterns of failure, and survival. Methods and Materials: Under an institutional review board-approved protocol, we retrospectively studied patients with LAPC treated with chemoradiation. Statistical models were used to test associations between clinical characteristics and outcomes, including upper GI bleeding, radiation treatment breaks, and weight loss during therapy. Results: Between 1999 and 2012, 211 patients were treated with radiation for pancreatic cancer. All patients received concurrent chemotherapy with either gemcitabine (174) or 5-fluorouracil (27), and 67 received intensity modulated radiation therapy (IMRT). Overall, 18 patients experienced an upper GI bleed related to treatment, with 70% of bleeds occurring in the stomach or duodenum, and among those patients, 11 (61%) patients had a pancreatic head tumor and 17 (94%) patients had a metallic biliary stent. IMRT was associated with decreased risk of postradiation nausea (odds ratio, 0.27 [0.11, 0.67], P = .006) compared with 3-dimensional conformal radiation. Regarding long-term toxicities, patients with a metallic biliary stent at the time of radiation therapy were at a significantly higher risk of developing upper GI bleeding (unadjusted hazard ratio [HR], 15.41 [2.02, 117.42], P = .008), even after controlling for radiation treatment modality and prescribed radiation dose (adjusted HR, 17.38 [2.26, 133.58], P = .006). Furthermore, biliary stent placement was associated with a higher risk of death (HR, 1.99 [1.41, 2.83], P < .001) after adjusting for demographic, treatment-related, and patient-related variables. Conclusions: Metallic biliary stents may be associated with an increased risk of upper GI bleeding and mortality. Furthermore, IMRT was associated with less nausea and short-term toxicity compared with 3-dimensional conformal therapy.

Stereotactic body radiation therapy (SBRT) following Yttrium-90 (90Y) selective internal radiation therapy (SIRT): a feasibility planning study using90Y delivered dose.

Objective.90Y selective internal radiation therapy (SIRT) treatment of hepatocellular carcinoma (HCC) can potentially underdose lesions, as identified on post-therapy PET/CT imaging. This study introduces a methodology and explores the feasibility for selectively treating SIRT-underdosed HCC lesions, or lesion subvolumes, with stereotactic body radiation therapy (SBRT) following post-SIRT dosimetry.Approach. We retrospectively analyzed post-treatment PET/CT images of 20 HCC patients after90Y SIRT. Predicted tumor response from SIRT was quantified based on personalized post-therapy dosimetry and corresponding response models. Predicted non-responding tumor regions were then targeted with a hypothetical SBRT boost plan using a framework for selecting eligible tumors and tumor subregions. SBRT boost plans were compared to SBRT plans targeting all tumors irrespective of SIRT dose with the same prescription and organ-at-risk (OAR) objectives. The potential benefit of SIRT followed by a SBRT was evaluated based on OAR dose and predicted toxicity compared to the independent SBRT treatment.Main results. Following SIRT, 14/20 patients had at least one predicted non-responding tumor considered eligible for a SBRT boost. When comparing SBRT plans, 10/14 (71%) SBRTboostand 12/20 (60%) SBRTaloneplans were within OAR dose constraints. For three patients, SBRTboostplans were within OAR constraints while SBRTaloneplans were not. Across the 14 eligible patients, SBRTboostplans had significantly less dose to the healthy liver (decrease in mean dose was on average ± standard deviation, 2.09 Gy ± 1.99 Gy, ) and reduced the overall targeted PTV volume (39% ± 21%) compared with SBRTalone.Significance. A clinical methodology for treating HCC using a synergized SIRT and SBRT approach is presented, demonstrating that it could reduce normal tissue toxicity risk in a majority of our retrospectively evaluated cases. Selectively targeting SIRT underdosed HCC lesions, or lesion subvolumes, with SBRT could improve tumor control and patient outcomes post-SIRT and allow SIRT to function as a target debulking tool for cases when SBRT is not independently feasible.

Does Vascular Collapse Occur After Treatment of Hepatocellular Cancer With Stereotactic Body Radiation Therapy?

There is debate about why stereotactic body radiation therapy (SBRT) produces superior control of hepatocellular cancer (HCC) compared to fractionated treatment. Both preclinical and clinical evidence has been presented to support a "classic" biological explanation: the greater BED of SBRT produces more DNA damage and tumor cell kill. More recently, preclinical evidence has supported the concept of a "new biology", particularly radiation-induced vascular collapse, which increases hypoxia and free radical activation. This is hypothesized to cause much greater tumor cell death than was produced by the initial radiation-induced DNA damage to the tumor. We decided to investigate if vascular collapse occurs after standard SBRT for patients with HCC. Eight patients with 10 lesions underwent dynamic contrast enhanced MRI at the time of simulation and either 48 or 96 hours after the first fraction. Only three of 10 tumors showed a decrease in blood flow. These findings suggest that vascular collapse does not typically occur after SBRT for HCC.