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The frequency of lymphocytes infiltrating tumors is a known prognostic in estrogen receptor (ER) negative cancers. ER+ disease is putatively believed to be immune cold, however, there exists a subset of ER+ tumors with high immune infiltrate and with a significant spatial heterogeneity. The clinic impact of such infiltrate - especially between the Oncotype Dx Recurrence Score risk categories - remains unclear. Moreover, the distribution of tumor and stromal tissues, while noted as significantly heterogenous, is still ill-defined and not yet clinically used prognostically, despite evidence to support its utility. Using a cohort (n=450) of serial sections taken from early-stage, ER+/HER2- breast tumors of the Irish arm of the TAILORx clinical trial, we aimed to investigate the tumor architecture and spatial distribution of tumor immune infiltrate and proliferating tumor cells using digital image analysis. Antibodies against Ki67 (proliferation marker) and CD45 (leukocyte common antigen), and a routine Haematoxylin and Eosin stain were applied to serial sections of 450 full-face tumors via chromogenic immunohistochemistry, as outlined previously [1]. Digital image analysis was performed using open-source software, QuPath [2]. Pixel classifiers were trained and validated against an expert pathologist in order to define observed lymphocytes as tumor or stromal-infiltrating, and to establish a classifier to quantify the tumor-stroma ratio (TSR) and infiltrating tumor area. Distances of CD45-positive cells from tumor were computed, along with autocorrelation statistics [3,4] of CD45 and Ki67 hotspots; firstly in order to quantify spatial heterogeneity, and secondly to examine whether Ki67 as a component gene in the Oncotype Dx assay has a foundation in tumor biology or is being confounded by potentially Ki67-positive lymphocytes. Subdividing by Oncotype Dx risk categories, no significant difference in TSR was observed (p=0.09799), neither for intermediary risk patients receiving hormone therapy alone or in combination with chemotherapy (p=0.3873). While there was an observed trend overall (p=0.092), no significance was found for recurrence between intermediary risk subcategories (HT alone: p=0.393, HT+CT: p=0.288). However, in the cohort as a whole, median TSR was 0.3215 (range 0 - 5.023), with statistically significant differences in recurrence risk observed (cohort high v low by median TSR. HR: 6.356, 95CI: 2.263-17.84, p Citation Format: Zak Kinsella, Anna Blümel, Mairi Lucas, Andreas Lindner, Claudia A. Gonzalez, Arman Rahman, Joanna Fay, Tony O'Grady, Verena Murphy, John Crown, Cathy Kelly, William Gallagher, Darran O'Connor. Modelling the spatial heterogeneity of CD45-positive tumor infiltrating lymphocytes in early-stage, estrogen receptor-positive breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5787.

Summary Background Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. Methods This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498. Findings Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2–10·7) with pembrolizumab and 8·3 months (7·6–9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66–1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4–2·0) with pembrolizumab and 4·1 months (3·1–4·2) with paclitaxel (HR 1·27, 95% CI 1·03–1·57). In the total population, grade 3–5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. Interpretation Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co.

Authors from New York present their experience of elective varicocelectomy, using microsurgical techniques, in a large series of children. They found the procedure to be safe and effective, and gave a much lower complication rate than the published rate in open varicocelectomy. The results of urethroplasty in post-traumatic paediatric urethral strictures are presented by authors from Mansoura. They found the overall success of one-stage perineal anastomotic repair of such strictures to be excellent, with very little morbidity. OBJECTIVE To report our experience of microsurgical subinguinal varicocelectomy in boys aged ≤ 18 years. PATIENTS AND METHODS Boys aged ≤ 18 years treated with microsurgical varicocelectomy between 1996 and 2000 at one institution were retrospectively reviewed. Indications for surgery included ipsilateral testicular atrophy, large varicocele or pain. Microsurgery was assisted by an operating microscope (×10–25) allowing preservation of the lymphatics, and the testicular and cremasteric arteries. Patient age, varicocele grade, complications and follow-up interval were recorded. RESULTS In all there were 97 microsurgical subinguinal varicocelectomies (23 bilateral) in 74 boys (mean age 14.7 years). Left-sided varicoceles were significantly larger (mean grade 2.9) than right-sided (mean grade 1.4) varicoceles. The mean follow-up was 9.6 months. There were four complications: two hydroceles, of which one resolved spontaneously after 4 months; one patient had persistent orchialgia that resolved after 8 months; and one developed hypertrophic scarring at the inguinal incision site. There were no infections, haematomas or intraoperative injuries to the vas deferens or testicular arteries. All boys were discharged home on the day of surgery. CONCLUSIONS Microsurgical subinguinal varicocelectomy in boys is a safe, minimally invasive and effective means of treating varicoceles. Compared with published results of the retroperitoneal mass ligation technique, which has a 15% overall complication rate and a 7–9% hydrocele occurrence rate, the microsurgical subinguinal approach appears to offer less morbidity, with a 1% hydrocele rate. We consider that microsurgical subinguinal varicocelectomy offers the best results with lower morbidity than other techniques.

© 2013 Chow et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: The prevalence of heart failure (HF) is rising in industrialized and developing countries. Though invasive coronary angiography (ICA) remains the gold standard for anatomical assessment of coronary artery disease in HF patients, alternatives are being sought. Computed tomographic coronary angiography (CTA) has emerged as an accurate non-invasive diagnostic tool for coronary artery disease (CAD) and has been demonstrated to have prognostic value. Whether or not CTA can be used in HF patients is unknown. Acknowledging the aging population, the growing prevalence of HF and the increasing financial burden of healthcare, we need to identify non-invasive diagnostic tests that are available, safe, accurate and cost-effective. Methods/Design: The proposed study aims to provide insight into the efficacy of CTA in HF patients. A multicenter randomized controlled trial will enroll 250 HF patients requiring coronary anatomical definition. Enrolled patients will be randomized to either CTA or ICA (n = 125 per group) as the first test to define coronary anatomy. The primary outcomes will be collected to determine downstream resource utilization. Secondary outcomes will include the composite clinical events and major adverse cardiac events. In addition, the accuracy of CTA for detecting coronary anatomy and obstruction will be assessed in patients who subsequently undergo both CTA and ICA. It is expected that CTA will be a more cost-effective strategy for diagnosis: yielding similar outcomes with fewer procedural risks and improved resource utilization. Trial registration: ClinicalTrials.gov, NCT01283659 Team grant #CIF 99470

Reperfused myocardium post-acute myocardial infarction (AMI) may have altered metabolism with implications for therapy response and function recovery. We explored glucose utilization and the “reverse mismatch” (RMM) pattern (decreased F-18-fluorodeoxyglucose (FDG) uptake relative to perfusion) in patients who underwent mechanical reperfusion with percutaneous coronary intervention (PCI) for AMI. Thirty-one patients with anterior wall AMI treated with acute reperfusion, with left ventricular ejection fraction ≤45%, underwent rest rubidium-82 (Rb-82) and FDG PET 2-10 days post-AMI. Resting echocardiograms were used to assess wall motion abnormalities. Significant RMM occurred in 15 (48%) patients and was associated with a shorter time to PCI of 2.9 hours (2.2, 13.3 hours) compared to patients without significant RMM: 11.4 hours (3.9, 22.4 hours) (P = .03). Within the peri-infarct regions, segments with significant RMM were more likely to have wall motion abnormalities (OR = 2.3 (1.1, 4.7), P = .02) compared to segments without significant RMM. RMM is a common pattern on perfusion/FDG PET during the sub-acute phase following reperfusion of AMI and is associated with shorter times to PCI. Within the peri-infarct region, RMM occurs frequently and is more often associated with wall motion abnormalities than segments without RMM. Whether this represents a myocardial metabolic shift during the sub-acute phase of recovery warrants further study.

Background: It has been hypothesized that [18F]-sodium fluoride (NaF) uptake imaged with positron emission tomography (PET) binds to hydroxyapatite molecules expressed in regions with active calcification. Therefore, we aimed to validate NaF as a marker of hydroxyapatite expression in high-risk carotid plaque. Methods: Eleven patients (69 ± 5 years, 3 female) scheduled for carotid endarterectomy were prospectively recruited for NaF PET/CT. One patient received a second contralateral endarterectomy; two patients were excluded (intolerance to contrast media and PET/CT misalignment). The bifurcation of the common carotid was used as the reference point; NaF uptake (tissue to blood ratio - TBR) was measured at every PET slice extending 2 cm above and below the bifurcation. Excised plaque was immunostained with Goldner’s Trichrome and whole-slide digitized images were used to quantify hydroxyapatite expression. Pathology was co-registered with PET. Results: NaF uptake was related to the extent of hydroxyapatite expression (r=0.45, pConclusion: NaF uptake is related to hydroxyapatite expression and is increased in plaque associated with cerebrovascular events. NaF may serve as a novel biomarker of active calcification and plaque vulnerability.

Purpose: Prolonged urinary retention remains a controversial and feared complication following bilateral extravesical ureteral reimplantation. We report a modified approach to limit detrusor nerve damage during extravesical correction of bilateral ureteral reflux that significantly reduces this adverse outcome. Materials and Methods: A modified approach to the distal detrusor dissection and ureteral mobilization, along with limited periureteral dissection, was used to perform this technique. A retrospective review of 50 patients undergoing bilateral nerve sparing extravesical ureteral reimplantation (NSEVR) by a single surgeon between 1997 and 2002 was completed. Patient age, vesicoureteral reflux (VUR) grade, length of hospital stay, length of surgery and outcome were evaluated. Results: The study included 36 girls and 14 boys, with an average age of 4 years 11 months (range 1 to 14 years). Average preoperative VUR grade was 2.61 (range 1 to 5). Average length of surgery when NSEVR was the only procedure performed was 105 minutes (range 54 to 185) and average length of hospital stay was 1.76 days (0 to 3). Transient urinary retention developed in 1 child on postoperative day 1, with a successful trial of voiding the next day. The rate of immediate urinary retention was 2%. There was no long-term urinary retention, voiding dysfunction or urinary tract infections. Conclusions: NSEVR for the correction of bilateral VUR is a simple modification that provides a reproducible and minimally invasive approach to treatment. We believe that limited distal ureteral dissection, preservation of the medial ureterovesical hiatus and judicious manipulation of the surrounding tissues result in elimination of long-term urinary retention.