Distal Location Research Articles

Acute Toxicities and Short-Term Follow-up of 64 Patients Treated with Intensity-Modulated Proton Beam Radiotherapy (IMPT) or Intensity-Modulated Photon Radiotherapy (IMRT) for Esophageal Carcinoma (EC): A Single-Center Experience

IMPT allows for a significant dosimetric advantage over IMRT in patients (pts) with EC, particularly for sparing the heart and lungs. However, increased uncertainties are associated with IMPT, such as organ motion and robustness. We present a clinical comparison of acute RT-related toxicities and short-term outcomes of pts treated with IMPT and IMRT for EC at our institution. A retrospective review was conducted on consecutive pts who underwent concurrent chemoradiation using IMPT or IMRT for EC with definitive or neoadjuvant intent from 2014-2018. Patient, treatment, toxicity, and disease outcome characteristics were extracted from medical records. Univariate and multivariate (MVA) analyses were performed (categorical variables by Fischer’s exact test and continuous variables by Wilcoxon-rank sum test). Survival outcomes were estimated by the Kaplan-Meier method. Sixty-four (32 per group) pts were included, with 10 months median follow-up for IMPT and 14 months for IMRT. Baseline characteristics were similar between groups except for (IMPT vs IMRT, respectively): dysphagia on presentation (85 vs. 63%, P=0.04) and histology (adenoma. 63 vs. 91%, P=0.02). Pts were more commonly male, with median age 72, ECOG 0-1, and distal tumor location (none statistically significant between IMPT and IMRT). Treatment intent was primarily neoadjuvant (72% IMPT, 81% IMRT) with the most common concurrent chemotherapy regimen being weekly carboplatin/paclitaxel (95% per group). The most common radiation regimen was 50 Gy in 25 fractions (75% IMPT, 78% IMRT). There was no significant difference in number of pts who underwent surgery (47% IMPT, 56% IMRT) and of those, no difference in pathologic complete response rates (33% IMPT, 39% IMRT). Post-operative complications were also similar between groups including pneumonia, anastomotic leak, anastomotic stricture, and cardiac arrhythmia rates. At one year, clinical outcomes were (for IMPT vs IMRT, respectively): local control 92 vs 84%, local-regional control 92 vs 80%, distant metastasis-free survival 87 vs 65%, and overall survival 74 vs 71% (none statistically significant between groups). IMPT pts had statistically significantly improved progression free survival (PFS) (75% vs 47%, P=0.02), and it remained significant for improved PFS in the final MVA model (P=0.04). No statistically significant association was seen between the two groups for acute treatment-related grade 3 toxicities (P=0.47). We report early, promising retrospective evidence for safety and efficacy of IMPT compared to IMRT for EC. Direct comparative studies of IMPT vs. IMRT utilizing prospective trials accruing larger, balanced patient cohorts are warranted in the future.

Incomplete atypical femoral fractures after bisphosphonate use in postmenopausal women.

This study aimed to determine the prevalence of incomplete atypical femoral fractures (iAFFs) in postmenopausal women using bisphosphonates and to investigate the potential risk factors for the development of iAFF. The national health-care records system indicated that 2746 postmenopausal women in our region aged ≥50 years were taking bisphosphonates. Using an assumed iAFF prevalence of 10% and levels of 5% α significance and ±5% precision, we calculated that a sample size of 132 participants was needed for this study. The patients were randomly selected and invited to the hospital. Radiographs and bone scans were used to evaluate each patient for iAFF. Bone mineral density, 25-hydroxy vitamin D, parathyroid hormone, and alkaline phosphatase measurements were performed. The mean age of the study population was 72.79 ± 7.35 years, and the mean duration of bisphosphonate use was 7.7 ± 3.4 years. We found iAFF in 14 (10.6%) patients, and 3 patients had bilateral involvement. Of the 17 femurs with iAFF, a proximal third location was seen in 2 patients (11.8%), a mid-third location in 14 (82.4%), and a distal third location in 1 (5.9%). The duration of bisphosphonate use was longer, and parathyroid hormone levels were higher in patients with iAFF compared to those without an incomplete fracture. We found a relatively higher prevalence of iAFF in postmenopausal women using bisphosphonate. Early identification and treatment of iAFF is crucial for reducing potential patient morbidity and hospital costs.

Multi-Institutional Evaluation of Curative Intent Chemoradiotherapy for Patients with Clinical T1N0 Esophageal Adenocarcinoma

To evaluate adverse events (AEs) and oncologic efficacy associated with curative-intent chemoradiotherapy (CRT) for patients with clinical T1N0 esophageal adenocarcinoma. This was a retrospective cohort study of patients with T1N0 adenocarcinoma of the esophagus treated with curative-intent CRT between 2004 and 2017 at two tertiary care centers. Toxicities were evaluated according to Common Terminology Criteria for AEs version 4.The Kaplan-Meier method was used to estimate overall (OS), progression-free (PFS), and disease-specific (DSS) survivals. A total of 28 patients were included for analysis. Patients did not undergo esophagectomy either due to medical comorbidity (54%) or patient preference (46%). The majority of patients were male (93%) and had a history of Barrett’s esophagus (71%). Median age was 76 (range 55-90), median Charlson Comorbidity Index was 1 (range 0-6), and baseline Eastern Cooperative Oncology Group performance status was 0 (57%) or 1-2 (43%). Tumor characteristics included distal esophagus location in 93%, clinical stage T1b in 86%, and median length of 2 cm (range 1-9). Tumor grade was 2 (54%) or 3 (46%). Treatment prior to CRT included endoscopic resection (ER) (57%) or induction chemotherapy (4%). Of those who underwent ER, 88% had a positive margin for invasive disease and 32% had pathologic evidence of lymphovascular invasion. Median RT dose was 50.4 Gy (range 40-50.4) in 28 fractions. RT techniques included 3D (32%), intensity modulated radiotherapy (43%), or proton therapy (25%). Concurrent chemotherapy was given to all patients, most commonly with 5-fluorouracil and taxane (43%) or platinum and taxane (29%) based regimens. Median follow-up was 44 months (range 4-146). Acute and late grade 3 gastrointestinal AEs were 18% and 7%, respectively. There were no grade 4 AEs. One patient died from treatment complications. Eight patients (29%) had disease progression at a median of 7.6 months after CRT. First site of progression was local in 4 (14%), local and regional in 3 (11%), or distant in 1 (4%). Salvage local treatment was performed in 3 patients, and included cryotherapy (n=1), ER + cryotherapy (n=1), or esophagectomy (n=1). The 3-year OS, PFS, and DSS were 78%, 62% and 81%, respectively. Tumor length > 2 cm was associated with worsened 3-year PFS (Hazard Ratio [HR]: 3.3, 95% confidence interval [CI]: 1.1-10.3) and 3-year DSS (HR 5.5, 95%CI: 1.04-29.4). Chemoradiotherapy is a safe and effective curative treatment strategy for select patients with clinical T1N0M0 esophageal adenocarcinoma.

Somatostatin-Expressing Interneurons Form Axonal Projections to the Contralateral Hippocampus.

Conscious memories are critically dependent upon bilateral hippocampal formation, and interhemispheric commissural projections made by mossy cells and CA3 pyramidal cells. GABAergic interneurons also make long-range axonal projections, but little is known regarding their commissural, inter-hippocampal connections. We used retrograde and adeno-associated viral tracing, immunofluorescence and electron microscopy, and in vitro optogenetics to assess contralateral projections of neurochemically defined interneuron classes. We found that contralateral-projecting interneurons were 24-fold less common compared to hilar mossy cells, and mostly consisted of somatostatin- and parvalbumin-expressing types. Somatostatin-expressing cells made denser contralateral axonal projections than parvalbumin-expressing cells, although this was typically 10-fold less than the ipsilateral projection density. Somatostatin-expressing cells displayed a topographic-like innervation according to the location of their somata, whereas parvalbumin-expressing cells mostly innervated CA1. In the dentate gyrus molecular layer, commissural interneuron post-synaptic targets were predominantly putative granule cell apical dendrites. In the hilus, varicosities in close vicinity to various interneuron subtypes, as well as mossy cells, were observed, but most contralateral axon varicosities had no adjacent immunolabeled structure. Due to the relative sparsity of the connection and the likely distal dendritic location of their synapses, commissural projections made by interneurons were found to be weak. We postulate that these projections may become functionally active upon intense network activity during tasks requiring increased memory processing.

The Efficacy of Early Extracorporeal Shockwave Lithotripsy for the Treatment of Ureteral Stones.

To determine the efficacy of early extracorporeal shockwave lithotripsy (e-ESWL) in colic patients with ureteral stones and the patient criteria for the most effective e-ESWL. 335 patients who received ESWL due to ureteral stone, were divide in two groups: e-ESWL and d-ESWL by the critical cut-off point. we performed the sensitivity and specificity cut-off analyses to identified the critical cut off point. To assess the difference in the factors affecting ESWL success, univariate and multivariate logistic analyses were implemented with using variables: ESWL success; age; gender; BMI; comor-bidity; serum creatinine; stone size; stone location; stone laterality; Hounsfield unit (HU); presence of hydrone-phrosis; and presence of tissue rim. The subgroup analysis for the screened variables was conducted. Optimal e-ESWL was defined to occur within a 24-hour critical cut-off time. Multivariate regression anal-ysis concluded with screened variables: age, stone size, stone location, and HU, that ESWL success was 1.85-fold higher in the e-ESWL patient group. The subgroup analyses the following conditions: ? 65 years old by 1.784- fold; ?10 mm stone size by 1.866-fold; mid to distal stone location by 2.234-fold; and ? 815 HU by 2.130-fold. When all the conditions were met, the e-ESWL success was 3.22-fold higher. In case of colic due to ureteral stones, the patient is recommended to receive a lithotripsy within the first 24 hours. E-ESWL is recommended especially in patients who are ? 65 years, or with a ureteral stone HU ? 815, sized ? 10 mm, or in a mid to distal location.

Thrombus Imaging Characteristics and Outcomes in Acute Ischemic Stroke Patients Undergoing Endovascular Treatment.

Background and Purpose- Thrombus imaging characteristics have been reported to be useful to predict functional outcome and reperfusion in acute ischemic stroke. However, conflicting data about this subject exist in patients undergoing endovascular treatment. Therefore, we aimed to evaluate whether thrombus imaging characteristics assessed on computed tomography are associated with outcomes in patients with acute ischemic stroke treated by endovascular treatment. Methods- The MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry is an ongoing, prospective, and observational study in all centers performing endovascular treatment in the Netherlands. We evaluated associations of thrombus imaging characteristics with the functional outcome (modified Rankin Scale at 90 days), mortality, reperfusion, duration of endovascular treatment, and symptomatic intracranial hemorrhage using univariable and multivariable regression models. Thrombus characteristics included location, clot burden score (CBS), length, relative and absolute attenuation, perviousness, and distance from the internal carotid artery terminus to the thrombus. All characteristics were assessed on thin-slice (≤2.5 mm) noncontrast computed tomography and computed tomography angiography, acquired within 30 minutes from each other. Results- In total, 408 patients were analyzed. Thrombus with distal location, higher CBS, and shorter length were associated with better functional outcome (adjusted common odds ratio, 3.3; 95% CI, 2.0-5.3 for distal M1 occlusion compared with internal carotid artery occlusion; adjusted common odds ratio, 1.15; 95% CI, 1.07-1.24 per CBS point; and adjusted common odds ratio, 0.96; 95% CI, 0.94-0.99 per mm, respectively) and reduced duration of endovascular procedure (adjusted coefficient B, -14.7; 95% CI, -24.2 to -5.1 for distal M1 occlusion compared with internal carotid artery occlusion; adjusted coefficient B, -8.5; 95% CI, -14.5 to -2.4 per CBS point; and adjusted coefficient B, 7.3; 95% CI, 2.9-11.8 per mm, respectively). Thrombus perviousness was associated with better functional outcome (adjusted common odds ratio, 1.01; 95% CI, 1.00-1.02 per Hounsfield units increase). Distal thrombi were associated with successful reperfusion (adjusted odds ratio, 2.6; 95% CI, 1.4-4.9 for proximal M1 occlusion compared with internal carotid artery occlusion). Conclusions- Distal location, higher CBS, and shorter length are associated with better functional outcome and faster endovascular procedure. Distal thrombus is strongly associated with successful reperfusion, and a pervious thrombus is associated with better functional outcome.

Sedimentary characteristics of hyperpycnites in a shallow lacustrine environment: A case study from the Lower Cretaceous Xiguayuan Formation, Luanping Basin, Northeast China

Hyperpycnites are extrabasinal turbidites related to hyperpycnal flows which form during river floods. Compared to intrabasinal turbidite systems in deep marine or lacustrine settings, hyperpycnites in shallow lakes settings are not understood. In this work, we studied the typical sedimentary characteristics of shallow lacustrine hyperpycnal flow deposits in outcrops of the Luanping Basin, Northeast China. Based on the sedimentary architecture and analysis of the facies associations in these outcrops, the hyperpycnites can be classified into the following three types: (a) bedload‐dominated erosional channel deposits, (b) bedload‐ and suspended‐load‐dominated channel‐to‐lobe transitional deposits, and (c) suspended‐load‐dominated lobe deposits. The erosional channels in proximal locations are filled by mud clasts, parallel‐laminated sandstones, massive sandstones, cross‐bedded sandstones, massive siltstones, and mudstones. The channel‐to‐lobe transitional deposits in a middle location are composed of parallel‐laminated sandstones, cross‐bedded sandstones, mud clasts near internal erosional surfaces, ripple cross‐bedded sandstones, massive siltstones, and mudstones. The lobe deposits in distal locations are composed of ripple cross‐bedded sandstones, massive siltstones, and mudstones. The sedimentary process of the shallow lacustrine hyperpycnal flows shows obvious response to periodic flood energy fluctuations. Gentle slope, small capacity of flood discharges and semiarid paleoclimate may be the possible reason for the observed sedimentary architecture of the shallow lacustrine hyperpycnal flow deposits. Therefore, this study offers new insights into the sedimentology of shallow lacustrine deposits in rift basins.

Radiological diagnosis of chronic recurrent multifocal osteomyelitis using whole-body MRI-based lesion distribution patterns

To explore the distribution patterns and extent of chronic recurrent multifocal osteomyelitis (CRMO) using whole-body magnetic resonance imaging (WBMRI). Children with established diagnoses of CRMO, who had undergone WBMRI, had their images reviewed by three radiologists using a novel pictorial mapping system for determining lesion load and distribution patterns. Thirty-seven children (mean 12 years; range 2-18 years) had 317 lesions (8.6 lesions per patient [LPP]; range 2-27). Multifocal involvement was noted in 33 (89%) and unifocal in four (11%). The tibia was most frequently involved (68% of patients; 29% of lesions). Clavicular involvement was noted in 38% and spinal lesions in 19% of patients. Bilateral disease involved the fibulas (80%), tibias (68%), and foot phalanges (67%) most frequently. In 93% of bilateral disease, there was also symmetry. A "tibio-appendicular multi-focal pattern" (tibial but no clavicular involvement) was present in 54% whereas a "claviculo-spinal pauci-focal pattern" (clavicular lesions, no tibial involvement; few additional lesions mainly of the spine) was present in 24%. Only 14% had synchronous involvement of the clavicle and tibia. In the long bones, 65% of lesions were metaphyseal (distal metaphysis 42%) and 35% epiphyseal (173 peri-physeal lesions). Epiphyseal lesions were minimal in 60% whereas metaphyseal lesions were extensive in 75%. Sixty-six percent of tibial symmetric lesions and 100% of symmetric lesions of the radius, humerus, and ulna were of equal severity. CRMO lesions are often multifocal and can have typical long bone distal metaphyseal locations. Two main phenotypic patterns have emerged: multifocal predominantly tibial involvement or pauci-focal clavicular and spinal disease.

Molecular and pathological features in patients with gastric cancer in Argentina. Association between Epstein Barr Virus, MSI, PD-L1 expression and T-cells infiltration

Introduction: The incidence of gastric cancer (CG) in Argentina is about 3900 cases and 3200 deaths per year. In the recent molecular classification stand out among others, those tumors associated with Epstein Barr virus (EBV) infection and microsatellite instability (MSI). Both are associated with an increase in the lymphoid infiltrate and this tumor microenvironment has been related to an increase in the expression of PD-L1. The clinical relevance of these features remains unclear. The objective of this study is to evaluate the expression of EBV and MSI, to analyze the expression of PD-L1 together with the presence of CD3 and CD8 lymphocytes in the tumor microenvironment and to describe their relationship with clinical-pathological characteristics. Methods: We evaluated a cohort of 47 patients with gastric adenocarcinoma, without neoadjuvant treatment, who underwent curative surgery. Immunohistochemistry (IHC) for MLH1, PMS2, MSH2, MSH6, PD-L1, CD3 and CD8; MSI assay with BAT25, BAT26, NR21, NR24, and MONO27 markers, and qualitative detection of EBV were performed. Results: Qualitative PCR for EVB was positive in 21% (n = 10) of cases. MSI was identified in 8% (N = 4) cases. The status of MSI and EBV positive GC were mutually exclusive. Correlation between MSI and MMR deficiency by IHC was 100% (MLH1 and PMS2 loss in all cases). CG EBV positive and CG MSI were more frequent in male patients, older than 50 years and distal gastric localization. The intestinal histological type was the most frequent in CG MSI, whereas represented 50% in CG EBV cases. 50% of the GC EBV and 75% of the CG MSI showed a high density of tumor-infiltrating lymphocytes (TILs). PDL1 was positive in tumor cells and in infiltrating immune cells in 28% (n = 13) cases (6/10 CG-EVB positive, 2/4 CG-MSI and 5/33 CG-EVB negative / MSS). GCs EBV positive and CG MSI that expressed PD-L1 had a high density of CD3 T-lymphocytes in both intratumoral region and invasion margin but low for CD8 T lymphocytes. Conclusion: In our gastric patients, PD-L1 expression was associated with distinct molecular and histopathological features including a high density of CD3 T lymphocytes, MSI status, and EBV. These data could be relevant to identify potential candidate patients for immunotherapies.

Giant villous adenoma of rectum- what is the malignant potential and what is the optimal treatment? A case and review of literature

IntroductionVillous adenomas are dubiously benign lesions, which are difficult to interpret because of their malignant potential. Distal villous adenomas present with bleeding or mucus discharge. Giant adenomas are not amenable for endoscopic or transanal resection. Only few isolated cases have been reported by laparoscopic resection. We present our case of a circumferential giant villous adenoma of the rectum managed successfully by laparoscopic ultra-low anterior resection with colo-anal anastomosis with a review of literature in regard to their malignant potential.Case reportA 62-year-old lady presented with complaints of painless bleeding per rectum and a fleshy mass protruding from the anal canal which on digital rectal examination appeared a large soft velvety flat mass with mucus discharge. Colonoscopy showed circumferential irregular, friable, edematous mucosa in rectum extending for 15 cm. Computed tomography showed a large heterogeneously enhancing polypoid mass lesion in the rectal wall involving the entire rectum. The patient underwent laparoscopic low anterior resection with colo-anal anastomosis and protecting loop ileostomy. Histopathological examination of the resected specimen revealed villous adenoma of the rectum with moderate to severe dysplasia.DiscussionVillous adenomas are sessile growths lined by dysplastic glandular epithelium, whose risk of malignancy is especially high up to 50% when greater than 2 cm in size. Large size, villous content, and distal location are all associated with severe dysplasia in colorectal adenomas. Large villous rectal tumors, particularly of circumferential type pose a great challenge for endoscopic or transanal removal. Henceforth, open or laparoscopic surgery is required for these cases.ConclusionGiant rectal villous polyps are usually unresectable by endoscopic methods or transanal endoscopic microsurgery and are associated with a high rate of unsuspected cancer which requires a formal radical oncologic resection. As per current data, the combined risk of dysplasia/malignancy is about 83% with 50% risk of dysplasia and frank malignancy in 33% of cases of giant rectal villous adenomas of more than 8 cm in size. Laparoscopic colorectal resection is safe and effective.

Fossilised geothermal surface features of the Whitianga Volcanic Centre (Miocene), Coromandel Volcanic Zone, New Zealand: Controls and characteristics

The Late Miocene Whitianga Volcanic Centre of the Coromandel Volcanic Zone, North Island, New Zealand, is host to 18 known, siliceous and intensely silicified deposits including: silicified volcanics; sediments of inferred lacustrine, fluvial and mud pool origin; siliceous hot spring deposits, or sinters; and silicic veins. Collectively these siliceous and silicified deposits indicate past geothermal activity that occurred at the Earth's surface and in the shallow subsurface. Sinters, in particular, are of interest because they are derived from deep geothermal reservoirs and precipitate from discharged thermal fluids at the intersection of the water table with the land surface. However, some siliceous and silicified features in hydrothermal paleoenvironments have been misidentified as sinters. By studying textural types, distributions, structural setting, mineral paragenesis and trace elemental composition of the siliceous and silicified deposits in the Whitianga Volcanic Centre, it is possible to differentiate sinters and identify their spring-vent source areas (100–70 °C) from more distal thermal spring discharge locations (<70 °C to ambient), extent of hydrothermal alteration, and, in places, delineate zones of epithermal upflow where AuAg mineralisation may have occurred at depth. This has important implications for the exploration of mineralised epithermal ore deposits at local to regional scales, in particular for the Hauraki Goldfield of the Coromandel Volcanic Zone.

Microelectrode Neuronal Activity of the Internal Globus Pallidus in Dystonia Correlates with Postoperative Neuromodulation Effects and Placement of the Stimulation Electrode

BackgroundDeep brain stimulation (DBS) is emerging as a viable treatment option for selected patients with dystonia. Intraoperative extracellular microelectrode recordings (MER) are considered as the standard electrophysiological method for the precise positioning of the DBS electrode into the target brain structure. Accurate targeting of the permanent stimulation electrode into the Globus Pallidus internus (GPi) is key to positive long-term effects. The suitability of the location is peroperatively assessed by microelectrodes that register single-unit neuronal activity. The aim of this article is to analyse electrophysiological recordings of patient's neuronal activity with a focus on the identification of markers relevant to the patient's clinical state. MethodsIn this study, 13 patients chronically treated with double-sided DBS GPi were examined with a microrecording. The signal (24 kHz) processing, included bandpass filtering (0.5–5 kHz), automated detection of artefacts and feature extraction. Pre-processed signals were analysed by means of statistical learning. ResultsThe results show that the GPi was distinguished from its vicinity with p < 0.001 and 3 machine learning models AUCs had an accuracy of higher than 0.87. The observed biomarker, Hjort mobility, additionally correlated with the long-term neuromodulation effect (rho = −0.4; p < 0.05). Furthermore, we revealed a change of neural activity associated with the active distal DBS contact localization along the medio-lateral direction. ConclusionThis paper demonstrates the quantitative relationship between electrophysiological findings and the clinical effects of pallidal stimulation in dystonia and suggested objectification predictors of the effectiveness of this therapy.

Can negative ureteroscopy be predicted in ureteral stone treatment?

We aimed to evaluate factors predictive of negative ureteroscopy (URS) in ureteral stones. Patients who underwent URS between January 2007 and June 2018 were included in the study. Patients were divided into two groups: group 1- positive URS (841 patients); and group 2 -negative URS (75 patients). These two groups were compared in terms of demographic data, stone characteristics, and postoperative outcomes. The mean age of the study patients was 44.5±15.1 years. The absence of collecting system dilatation due to the present stone was found to be a significant predictive factor for negative URS in univariate analysis, but there was no significant difference in multivariate analysis. In the multivariate analysis, low body mass index (BMI), no history of stone surgery, stone located in the distal ureter, small stone area, longer time between the last imaging procedure and URS, and medical expulsive therapy (MET) application were statistically significant in predicting negative URS. In this study, the parameters that significantly predicted negative URS were found to be low BMI, no history of stone surgery, distal localization of the stone, small stone area, longer time between the last imaging procedure and URS, and MET applied for the current stone. These parameters should be considered to avoid negative URS and patients should be informed of the possibility of negative URS prior to operation.

Diagnostic Ultrasound Detection of Changes in Femoral Muscle Mass Recovery after Tibial Plateau Levelling Osteotomy in Dogs.

The goal of this study was to develop a clinically feasible ultrasound (US) protocol that can detect changes in thigh muscle mass in dogs after stifle surgery. The primary aim of this study was to compare previously described US measurement locations of the canine thigh for detecting changes in muscle mass in dogs recovering from tibial plateau levelling osteotomy (TPLO). This was a prospective, exploratory pilot study. Adult dogs (n = 7) undergoing pet-owner elected TPLO were enrolled. Twelve different US measurements were performed in triplicate by a single experienced observer. Measurements were performed at 0, 2, 4 and 8 weeks after surgery at a proximal and distal location along the femur. Data from all available time points and locations were analysed for the main effect of time within modalities. A total of 1,008 US measurements were performed. Measurements of the transverse sectional area of the rectus femoris muscle detected significant (p ≤ 0.05) muscle loss between weeks 0 and 2 at the lateral and medial aspects of the distal location (19% and 15% respectively). Measurements of the thigh muscle thickness were significantly (p < 0.01) increased between 2nd- and 8th- week time points at the lateral aspect of the proximal location (26%). The proximal femoral location, measured from the lateral aspect, appears to be the most suitable US measurement for detecting increases in femoral muscle mass in dogs recovering from TPLO. The provided pilot data suggest that further research evaluating this outcome measure is indicated.

NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)—First experimental arm (EA) initial results.

3505 Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of hypotheses in a consistent high-risk pt population with correlative biomarkers. Primary endpoint (EP) and available secondary EPs from the first EA using veliparib (a PARPi) are reported. NCT02921256. Methods: Stage II/III pts with LARC (with any ONE of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to neoadjuvant FOLFOX (x 4mo) → chemoRT (cape with 50.4Gy +/- veliparib 400mg PO BID) → surgery 8-12 wks later. Primary EP: 4 point reduction in Neoadjuvant Rectal Cancer (NAR) score with a one-sided α = 0.10 and 80% power. NAR compared by linear model controlling for stratification and possibly other factors. Secondary EPs: OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, and SSS. Binary EPs compared by Fisher’s exact test. Reported p-values are two-sided. Results: From 10/2016 - 2/2018, 178 pts were randomized (88 control, 90 veliparib). Baseline characteristics were balanced except for candidate for SSS at entry (39% control, 61% veliparib). 140 pts were evaluable for NAR (72 control, 68 veliparib). Mean NAR was 12.6 control (95% CI: 9.8–15.3) vs 13.7 for veliparib (CI: 10.2–17.2). Controlling for stratification (p = 0.69) or stratification and candidate for SSS (p = 0.78), NAR difference was not significant. pCR = 21.6% vs 33.8% (p = 0.14); cCR = 28.2% vs 33.3% (p = 0.60); and SSS = 52.5% vs 59.3% (p = 0.43). Most common grade 3/4 AEs were diarrhea and cytopenias. The EA had two deaths (cardiac arrest [FOLFOX]; enterocolitis [chemoRT]). Conclusions: Veliparib added to chemoRT as part of TNT was safe and without unexpected short-term toxicities but failed to improve the NAR score. Support: U10CA180868, -180822; UG1-189867; U24-196067; AbbVie. Clinical trial information: NCT02921256.

Defining an IBD-like subgroup in consensus molecular subgroups of colorectal cancer and transcriptomic biomarker development for at-risk patients.

e15142 Background: Ulcerative colitis (UC), is a known risk-factor for colorectal cancer (CRC). 10% of UC-patients develop UC-specific CRC yet there are currently no biomarkers for early detection or understanding of drivers of disease. Unresolved inflammation is key in UC-CRC development, yet the aetiology is unclear. It is unknown if UC-CRC falls into a specific consensus molecular subgroup in the CMS classification (Guinney et al 2015). This bioinformatics approach aimed to identify patients at-risk of developing UC-CRC, whilst informing biological and clinical understanding of the disease. Methods: We used publicly available UC data and in-silico, cross platform, class label transfer (GECA) to determine mRNA similarity between UC/UC-CRC and sporadic CRC (sCRC) and to identify a UC-predominant CMS. Pathogenic mutations were identified for each CMS as well as gene set enrichment and survival analysis to determine UC-CRC behaviour comparative to sCRC. Transcriptional relationships were assessed via unsupervised and semi-supervised clustering by immune-signatures and scores to determine molecular patterns between phenotypes. We derived a gene list from UC data informed by clustering to stratify patients based on risk to UC-CRC progression. Results: UC-CRC featured predominantly in the NA group, with 3 attributed pathogenic mutations, an oxidative stress environment and neuroendocrine dysregulation. The subgroup had UC-like clinical features; younger age, distal tumour location and TP53 mutations along with the highest rate of cancer recurrence (~20%) and a unique cellular composition in CMS being highly immune and stromal. Importantly this immune signal was distinct from the interferon type signalling observed in CMS1 and was not associated with PD-L1 activation. Clustering revealed a loss of IFN-type gene expression in colon tissue as UC progressed to UC-CRC. Conclusions: The NA group was thought to be unclassifiable samples between CMS however, analysis shows UC-CRC enrichment with defined biological characteristics. We have identified novel biology that may inform the risk of developing UC-CRC and guide potential preventative and therapeutic approaches.

Mutational signatures of early-onset colorectal cancer.

e15113 Background: Despite a reduction of Colorectal Cancer (CRC) incidence in western countries in the past decades, Early-Onset CRCs (EO-CRC, patients diagnosed with CRC ≤ 40 years old) incidence has increased. Although frequently occurring in the context of familial syndromes, EO-CRCs are mainly sporadic cases and phenotipically enriched for distal localisation and advanced stage at diagnosis. Whether EO-sporadic CRCs pathogenesis differs from that of normal-onset (NO) CRC and how this might impact incidence rates is currently unknown. This had prompted us to ask if, at the genetic level, “traces” of peculiar pathogenic processes could be identified in EO-specific (or -enriched) genetic signatures (GS). Methods: The mutational signatures of 424 TCGA CRC patient samples (19 EO and 405 ≥ 50 years at diagnosis) were analyzed and the similarity between each mutational profile and COSMIC GS was calculated using Bioconductor R package Mutational Patterns (doi: 10.1186/s13073-018-0539-0). Unsupervised hierarchical clustering of the samples according to similarity to GS was performed in single cohort and pooled analysis. Association between age and individual GS was assessed through grouped and linear correlation analysis. Results: EO-CRC patients were grouped in three main clusters: Cluster1 exposing a major similarity with GS10 (associated with defects in polymerase proofreading activity), Cluster2 showing stronger similarities with GS6 (associated with mismatch repair deficiency), and GS1 (associated with 5-MeC deamination) and Cluster3 presenting similarity with multiple GSs, such as 3 (associated with homologous recombination deficiency) and 5 (pathogenesis unknown). Overall this clustering was maintained when EO-CRC samples were pooled with NO CRC. Grouped and correlation analysis revealed no significant association between age and individual GSs, including GS1 (associated with age). Conclusions: These preliminary analyses show that the relative contribution of known GS is similar in EO and NO cohorts of patients. Possible enrichment for EO-CRC in specific signature clusters will be analysed on a wider sample series.

Treatment patterns and survival differ between early-onset and late-onset colorectal cancer patients: the patient outcomes to advance learning network.

Our objective was to describe differences in treatment patterns and survival between early-onset (< 50years old) and late-onset colorectal cancer (CRC) patients in community-based health systems. We used tumor registry and electronic health record data to identify and characterize patients diagnosed with adenocarcinoma of the colon or rectum from 2010 to 2014 at six US health systems in the patient outcomes to advance learning (PORTAL) network. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing the distribution of tumor characteristics and treatment patterns in early-onset versus late-onset CRC. Cox regression models were used to estimate adjusted hazard ratios (HRs) and CIs comparing survival between early- and late-onset CRC patients. There were 1,424 early-onset and 10,810 late-onset CRC cases in our analyses. Compared to late-onset CRC, early-onset CRC was significantly associated with advanced-stage disease, high-grade histology, signet ring histology, and rectal or left colon location. After adjusting for differences in tumor and patient characteristics, early-onset patients were more likely than late-onset patients to have > 12 lymph nodes examined (OR 1.60, CI 1.37-1.87), to receive systemic therapy (chemotherapy or immunotherapy) within 6months of diagnosis (OR 2.84, CI 2.40-3.37), and to have a reduced risk of CRC-specific death (HR 0.66, CI 0.56-0.79). Early-onset CRC is associated with aggressive tumor characteristics, distal location, and systemic therapy use. Despite some adverse risk factors, these patients tend to have better survival than older onset patients.

Time constraints on the closure of the Paleo–South China Ocean and the Neoproterozoic assembly of the Yangtze and Cathaysia blocks: Insight from new detrital zircon analyses

The South China Block was built up by the assembly of the Yangtze and Cathaysia blocks along the Neoproterozoic Jiangnan Orogenic Belt. The timing of the Jiangnan Orogeny remains controversial. The widespread orogeny–related Neoproterozoic angular unconformity that separates the underlying folded Sibao (ca.1000–820 Ma) and overlying Danzhou (ca.800–720 Ma) Groups was investigated. Six sedimentary samples, below and above the unconformity in three distal localities (Fanjingshan, Madiyi, and Sibao) yield detrital zircon with UPb ages ranging from 779 ± 16 Ma to 3006 ± 36 Ma, with a prominent peak at ca. 852 Ma. The youngest ages of 832 ± 11 Ma and 779 ± 16 Ma are revealed for the underlying Sibao and overlying Danzhou Groups, respectively. The detrital zircon UPb age relative probability plot of the Jiangnan Orogen matches well with those of the Yangtze and Cathaysia blocks since ca. 865 Ma. Integrating geological, geochemical and geochronological results, we suggest that the Paleo–South China Ocean began to subduct under the Yangtze block at ca. 1000 Ma, and was partly closed at ca. 865 Ma. Afterwards, the Yangtze and Cathaysia blocks initially collide at 865 Ma, forming the Jiangnan Orogen. This collision resulted in not only the folding of the Sibao Group, but also sediment deposition in a syn-collisional setting, which makes the upper part of the Sibao Group. The youngest S-type granite dated at ca. 820 Ma that intruded in the Sibao Group marks the late stage of the Jiangnan Orogeny.

‘I want the heart of fierceness to arise within us’: maintaining public space to promote HIV-related health with House Ball Community members in an era of gentrification

The House Ball Community consists of sexual, gender and ethnic minority youth who form family-like houses and compete in balls. Many rely on community-based organisations as venues for socialising and accessing health-related resources. In recent years, urban gentrification has challenged the economic survival of the organisations that serve this community and its members. Between 2016 and 2017, we conducted 45 in-depth interviews with houses and gay families in the San Francisco Bay Area and regular participant observation at community events, including balls. In addition to forcing community organisations to close or move, rising rents have increased housing instability among Ballroom Community members, with some moving to distal locations. Participants felt nostalgia for organisations that provided HIV-related services and hosted balls in previous years, feeling the loss of space keenly. To maintain community and generate employment, the San Francisco Ballroom Community now offers Vogue classes at private dance studios. This allows participants to recruit new house members, welcoming a broader array of individuals into the community than those who have historically participated. However, accessing culturally appropriate sexual health services remains difficult. Health advocates should recognise that community organisations are necessary for diverse youth to build community and access sexual health services.