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Background Outcomes for patients with metastatic renal cell carcinoma (mRCC) and tumour thrombus remain poor. Recent data suggest limited role for cytoreductive nephrectomy (CN) and data on thrombus response to systemic therapy (ST) is scarce. Here, we describe response and survival of patients with de novo mRCC and thrombi treated with ST with or without CN. Methods Demographics, disease characteristics and survival of patients with de novo mRCC were collected. Progression-free survival (PFS) and overall survival (OS) in months (m) was calculated using the Kaplan–Meier method (log-rank). Results Between 2002 and 2019, 226 patients with mRCC were identified, 64 (28.3%) had tumour thrombus out of which 18 (28.1%) received only ST. Among 12 evaluable patients, thrombus response, stability and progression were seen in 3 (25%), 6 (50%) and 3 (25%) patients, respectively. Median OS was similar for patients with and without tumour thrombus treated with systemic therapy alone [OS: 12.1 m (8.8–27.7) vs. 13.9 m (7.9–21.5), p = 0.87]. CN predicted for better OS in patients with tumour thrombus [OS: 29.4 m (17.4–48.9) vs. 12.1 m (8.8–27.7), p = 0.01]. Conclusion In this retrospective series of patients with mRCC and tumour thrombus, addition of CN to ST improved outcomes. Validation of these findings with contemporary regimens is needed.

Tumor markers alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase assume a key role in the management of testicular germ cell tumors. While alpha-fetoprotein and human chorionic gonadotropin have modest sensitivity and specificity for germ cell tumors, lactate dehydrogenase has weak sensitivity and specificity. We explored the utility of lactate dehydrogenase in identifying relapse among stage I seminomatous and nonseminomatous germ cell tumors on surveillance.Patients with a history of stage I testicular germ cell tumors were identified from a prospectively maintained database at the Princess Margaret Cancer Centre from December 1980 to May 2021 and surveyed according to established institutional algorithm guidelines. The utility of lactate dehydrogenase elevation to independently detect germ cell tumor relapse was examined.Among 1,014 seminoma and 676 nonseminomatous germ cell tumor patients, 176 and 176 patients relapsed with a median time to relapse of 13.6 and 8.9 months, respectively. Imaging alone was the most common mode of relapse detection in 144 and 74 of seminoma and nonseminomatous germ cell tumor patients, respectively. Lactate dehydrogenase was elevated in 49 cases of seminoma and 38 cases of nonseminomatous germ cell tumors at relapse, but was never the sole relapse indicator. Among 350 seminoma and 311 nonseminomatous germ cell tumor patients who never relapsed, 210 and 233, respectively, had at least 1 elevated lactate dehydrogenase value.Lactate dehydrogenase alone did not independently contribute to early relapse detection in stage I seminoma or nonseminomatous germ cell tumor. Elevated lactate dehydrogenase values were documented in a high proportion of nonrelapsing seminoma and nonseminomatous germ cell tumor cases.

We have recommended active surveillance as the preferred management option for clinical stage I (CSI) testicular germ cell tumors (GCTs) since 1980. Over time, the recommended intensity of surveillance has decreased; however, the impact on relapse detection has not been investigated.To examine relapse rate, time to relapse, extent of disease, and burden of treatment at relapse across decreasing surveillance intensity over time.CSI GCT patients under active surveillance from 1981 to 2021 were included in this study.Through four major iterations in both nonseminomatous (NSGCT) and seminoma surveillance schedules, visit frequency, blood testing, and imaging have been decreased successively. Low-dose, noncontrast computed tomography (CT) scans were adopted in 2011. Categorical variables and time to relapse were compared using chi-square and Fisher's exact or Kruskal-Wallis test, respectively.A total of 1583 consecutive patients (942 with seminoma and 641 with NSGCT) were included. In seminoma, chest x-rays were reduced from 13 to one and CT scans were reduced from 20 to ten. Relapse rate, time to relapse, N or M category, and International Germ Cell Cancer Collaborative Group (IGCCCG) classification did not change. In NSGCT, chest x-rays were reduced from 27 to zero and CT scans were reduced from 11 to five. Relapse rate (from 46.2% to 21.2%,Despite considerable reductions in surveillance intensity, we did not observe an increase in disease extent, treatment burden, or GCT cancer deaths upon relapse. These results support that our current lower-intensity active surveillance schedules are safe for managing CSI GCT.Our current reduced-intensity surveillance schedules for clinical stage I germ cell tumors appear to be safe.

ObjectivesMeasurement of Response Evaluation Criteria In Solid Tumors (RECIST) relies on reproducible unidimensional tumor measurements. This study assessed intraobserver and interobserver variability of target lesion selection and measurement, according to RECIST version 1.1 in patients with ovarian cancer.MethodsEight international radiologists independently viewed 47 images demonstrating malignant lesions in patients with ovarian cancer and selected and measured lesions according to RECIST V.1.1 criteria. Thirteen images were viewed twice. Interobserver variability of selection and measurement were calculated for all images. Intraobserver variability of selection and measurement were calculated for images viewed twice. Lesions were classified according to their anatomical site as pulmonary, hepatic, pelvic mass, peritoneal, lymph nodal, or other. Lesion selection variability was assessed by calculating the reproducibility rate. Lesion measurement variability was assessed with the intra-class correlation coefficient.ResultsFrom 47 images, 82 distinct lesions were identified. For lesion selection, the interobserver and intraobserver reproducibility rates were high, at 0.91 and 0.93, respectively. Interobserver selection reproducibility was highest (reproducibility rate 1) for pelvic mass and other lesions. Intraobserver selection reproducibility was highest (reproducibility rate 1) for pelvic mass, hepatic, nodal, and other lesions. Selection reproducibility was lowest for peritoneal lesions (interobserver reproducibility rate 0.76 and intraobserver reproducibility rate 0.69). For lesion measurement, the overall interobserver and intraobserver intraclass correlation coefficients showed very good concordance of 0.84 and 0.94, respectively. Interobserver intraclass correlation coefficient showed very good concordance for hepatic, pulmonary, peritoneal, and other lesions, and ranged from 0.84 to 0.97, but only moderate concordance for lymph node lesions (0.58). Intraobserver intraclass correlation coefficient showed very good concordance for all lesions, ranging from 0.82 to 0.99. In total, 85% of total measurement variability resulted from interobserver measurement difference.ConclusionsOur study showed that while selection and measurement concordance were high, there was significant interobserver and intraobserver variability. Most resulted from interobserver variability. Compared with other lesions, peritoneal lesions had the lowest selection reproducibility, and lymph node lesions had the lowest measurement concordance. These factors need consideration to improve response assessment, especially as progression free survival remains the most common endpoint in phase III trials.

Increasing globalization combined with crises that affect everyone, such as pandemics, climate change and armed conflicts, pose major challenges for value-based business ethics. Added to this is the enormous disparity between poor and rich people worldwide. It is no longer just the organizational power of the individual state that is needed, as the Jena-based entrepreneur Ernst Abbe assumed, but that of the global community in order to establish life-serving global regulations. In addition, the book shows how companies and managers can act and lead in a mindful and value-oriented manner under today's conditions.

Vaccine scarcity and availability distinguish two central ethics questions raised by the Covid-19 pandemic. First, in situations of scarcity, which groups of persons should receive priority? Second, in situations where safe and effective vaccines are available, what circumstances and reasons can support mandatory vaccination? Regarding the first question, normative approaches converge in prioritizing most-vulnerable groups. Though there is room for prudential judgement regarding which groups are most vulnerable, the human dignity principle is most relevant for prioritization consideration of both medical and non-medical issues. The second question concerning mandates is distinct from considerations about persons’ individual moral duty to receive vaccines judged reasonably safe and critical for individual and public health. While there is consensus regarding the potential normative support for mandated vaccination, the paternalistic government intervention of vaccine mandates requires a high bar of demonstrated vaccine safety and public health risk. We discuss stronger and weaker forms of paternalism to deal with the Covid-19 pandemic from an “integrative” approach that integrates leading normative approaches. We argue against a population-wide compulsory vaccination and support prudential measures to 1) protect vulnerable groups; 2) focus upon incentivizing vaccine participation; 3) maintain maximum-possible individual freedoms, and 4) allow schools, organizations, and enterprises to implement vaccine requirements in local contexts.

A 2020 decision by Germany’s highest court dramatically shifted the national discussion on assisted suicide. The decision stressed the ‘right to a self-determined death’ which must ‘be respected by state and society as an act of personal autonomy and self-determination’. Moreover, it clarified the non-criminality of assistance for suicides by third parties. The reaction of the main churches in Germany to this decision reflects ecclesiological differences. Protestant positions on assisted suicide are defined by pluralism; the Roman Catholic official position remains tied to ontologically-referenced principles of natural law that prohibit assisted suicide as intrinsically evil. Thus, ecumenical efforts on bioethics are complicated by a context where many Protestant leaders prioritize autonomy and pluralism, whereas Roman Catholic leaders stress consensus and orthodoxy. Even official church guidelines on such matters are received differently in Protestant and Roman Catholic communities. For Protestant Christians, an opinion functions primarily as guideline; for Catholic Christians, there is a goal at least of reaching principles reflecting the objective order of God’s creation.

PurposeGenetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of these findings. The genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis (ADAMS) project aims to gather genetic and phenotypic data on a large cohort of ancestrally-diverse individuals with MS living in the UK.ParticipantsAdults with self-reported MS from diverse ancestral backgrounds. Recruitment is via clinical sites, online (https://app.mantal.co.uk/adams) or the UK MS Register. We are collecting demographic and phenotypic data using a baseline questionnaire and subsequent healthcare record linkage. We are collecting DNA from participants using saliva kits (Oragene-600) and genotyping using the Illumina Global Screening Array V.3.Findings to dateAs of 3 January 2023, we have recruited 682 participants (n=446 online, n=55 via sites, n=181 via the UK MS Register). Of this initial cohort, 71.2% of participants are female, with a median age of 44.9 years at recruitment. Over 60% of the cohort are non-white British, with 23.5% identifying as Asian or Asian British, 16.2% as Black, African, Caribbean or Black British and 20.9% identifying as having mixed or other backgrounds. The median age at first symptom is 28 years, and median age at diagnosis is 32 years. 76.8% have relapsing–remitting MS, and 13.5% have secondary progressive MS.Future plansRecruitment will continue over the next 10 years. Genotyping and genetic data quality control are ongoing. Within the next 3 years, we aim to perform initial genetic analyses of susceptibility and severity with a view to replicating the findings from European-ancestry studies. In the long term, genetic data will be combined with other datasets to further cross-ancestry genetic discoveries.

Background: There has been a rapid increase in research applying artificial intelligence (AI) to various subspecialties of orthopaedic surgery, including foot and ankle surgery. The purpose of this systematic review is to (1) characterize the topics and objectives of studies using AI in foot and ankle surgery, (2) evaluate the performance of their models, and (3) evaluate their validity (internal or external validation). Methods: A systematic literature review was conducted using PubMed/MEDLINE and Embase databases in December 2022. All studies that used AI or its subsets machine learning (ML) and deep learning (DL) in the setting of foot and ankle surgery relevant to orthopaedic surgeons were included. Studies were evaluated for their demographics, subject area, outcomes of interest, model(s) tested, model(s)’ performance, and validity (internal or external). Results: A total of 31 studies met inclusion criteria: 14 studies investigated AI for image interpretation, 13 studies investigated AI for clinical predictions, and 4 studies were grouped as “other.” Studies commonly explored AI for ankle fractures, calcaneus fractures, hallux valgus, Achilles tendon pathologies, plantar fasciitis, and sports injuries. For studies reporting the area under the receiver operating characteristic curve (AUC), AUCs ranged from 0.64 (poor) to 0.99 (excellent). Two studies (6.45%) reported external validation. Conclusion: Applications of AI in the field of foot and ankle surgery are expanding, particularly for image interpretation and clinical predictions. Current model performances range from poor to excellent, and most studies lack external validation, demonstrating a need for further research prior to deploying AI-based clinical applications. Level of Evidence: Level III, retrospective cohort study.

Extension of tumor tissue within a vein is a recognized prognostic factor in abdominal malignancy because of its influence on tumor staging and selection of therapeutic management. With the advent of newer surgical techniques, and variable treatment strategies, imaging plays a crucial role in categorizing patients according to the tumor resectability and vascular reconstruction techniques during surgery. Understanding the clinical impact of tumor thrombus increases the awareness of the radiologist about the key findings in tumor staging and decision-making of surgical approach. Ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) can be used individually and in combination to accurately assess the tumor thrombus. In our pictorial review, we will discuss the imaging findings and clinical consequences of tumor thrombosis in abdominal malignancies, including hepatocellular carcinoma, pancreatic neuroendocrine tumor, renal cancer, and adrenal cortical carcinoma.

PURPOSE Active surveillance (AS) for testicular nonseminomatous germ cell tumors (NSGCT) is widely used. Although there is no consensus for optimal treatment at relapse on surveillance, globally patients typically receive chemotherapy. We describe treatment of relapses in our non–risk-adapted NSGCT AS cohort and highlight selective use of primary retroperitoneal lymph node dissection (RPLND). METHODS From December 1980 to December 2015, 580 patients with clinical stage I NSGCT were treated with AS, and 162 subsequently relapsed. First-line treatment was based on relapse site and extent. Logistic regression was used to explore factors associated with need for multimodal therapy on AS relapse. RESULTS Median time to relapse was 7.4 months. The majority of relapses were confined to the retroperitoneum (66%). After relapse, first-line treatment was chemotherapy for 95 (58.6%) and RPLND for 62 (38.3%), and five patients (3.1%) underwent other therapy. In 103 (65.6%), only one modality of treatment was required: chemotherapy only in 58 of 95 (61%) and RPLND only in 45 of 62 (73%). Factors associated with multimodal relapse therapy were larger node size (odds ratio, 2.68; P = .045) in patients undergoing chemotherapy and elevated tumor markers (odds ratio, 6.05; P = .008) in patients undergoing RPLND. When RPLND was performed with normal markers, 82% required no further treatment. Second relapse occurred in 30 of 162 patients (18.5%). With median follow-up of 7.6 years, there were five deaths (3.1% of AS relapses, but 0.8% of whole AS cohort) from NSGCT or treatment complications. CONCLUSION The retroperitoneum is the most common site of relapse in clinical stage I NSGCT on AS. Most are cured by single-modality treatment. RPLND should be considered for relapsed patients, especially those with disease limited to the retroperitoneum and normal markers, as an option to avoid chemotherapy.

Background Stage 3 pancreatic ductal adenocarcinoma (PDAC) is defined by arterial involvement. This study objective was to evaluate outcomes for patients with stage 3 PDAC with potentially reconstructable arterial involvement, considered for neoadjuvant therapy (NAT) and pancreatic resection, and to compare outcomes following arterial (AR) and non-arterial resection (NAR). Methods This study included patients from 2009 to 2016 with biopsy-proven stage 3 PDAC who were offered NAT before surgical exploration. AR was performed if required to achieve R0 resection. Time to event outcomes were analysed from diagnosis date. Results 87/89 patients (97.8%) received NAT (chemotherapy 41.6%, chemotherapy/radiotherapy 56.2%). 46/89 (51.7%) underwent exploration; 31 underwent resection (AR n = 20, NAR n = 11). AR patients had longer operative time (681 vs. 563 min, p = 0.006) and more blood loss (1600 vs. 575 mL, p = 0.0004), with no difference for blood transfusion, pancreatic fistula, length of stay, reoperation, or mortality. R0 rate was 30/31. Post-resection 90-day mortality was 3.2%. Median overall survival was statistically comparable between the AR and NAR groups (19.7 vs. 28.4 months, p = 0.41). Conclusions AR had comparable clinical and oncologic outcomes to NAR. Following careful selection and non-progression after NAT, major AR may cautiously be considered if required to obtain a negative resection margin.

Background Optimal management of clinical stage I (CSI) testicular cancer is controversial due to lack of robust prognostic factors; miRNA-371a-3p holds promise as a biomarker, although its clinical utility for identifying patients at risk of relapse is unknown. Objective To explore the association between serum miR-371a-3p and CSI surveillance relapse. Design, setting, and participants Serial banked sera from 151 CSI (101 seminomas and 50 nonseminomatous germ cell tumors [NSGCTs]) samples from our Princess Margaret active surveillance cohort were tested. Outcome measurements and statistical analysis Using the ampTSmiR test, miR-371a-3p was assayed. Multivariate logistic regression was used to assess the association between postorchiectomy miRNA and relapse. Results and limitations Thirty-four (23%) patients relapsed. There was no association between postorchiectomy miR-371a-3p (2.43 vs 2.74, p = 0.31) or percent decline from before to after orchiectomy (95.8% vs 93.1%, p = 0.14) and relapse. After adjustment for clinical prognostic factors, there remained no association between postorchiectomy miR-371a-3p and relapse (seminoma: odds ratio [OR] 1.33, 95% confidence interval [CI] 0.87–2.02, p = 0.18; NSGCT: OR 0.45, 95% CI 0.21–1.00, p = 0.05). Postorchiectomy miR-371a-3p levels rose as the date of miRNA assessment approached relapse. At relapse, serum markers alpha-fetoprotein and human chorionic gonadotropin were normal in 62%; yet, miR-371a-3p was elevated in 32/34 (94.1%). The magnitude of miR-371a-3p elevation at relapse correlated with disease burden (N1/M0 122.5 vs N2-N3/M0: 521.1; p = 0.05). Limitations include small numbers of relapses and variable time points of serum collection. Conclusions In our cohort of CSI testis cancer patients on surveillance, postorchiectomy miR-371a-3p levels were not associated with relapse, suggesting that miR-371a-3p may not be a useful biomarker for guiding adjuvant therapy. Our data suggest that miR-371a-3p holds potential as an early relapse marker and warrants a prospective study, as this may allow a window for less morbid relapse therapy. Patient summary The promising novel blood biomarker for testis cancer miR-371a-3p may not provide information at testicle removal, but serial monitoring may lead to earlier detection of relapse.

410 Background: Active surveillance (AS) for stage I germ cell tumor (GCT) typically includes periodic imaging of chest, abdomen and pelvis. Efforts to modify the surveillance protocols aim to minimize radiation exposure in this young patient population. We report our multi-institutional effort to assess the effect of omitting CT pelvis. Methods: Using data from three major referral centers for GCT (University of Southern California, University of Toronto, and University of Chicago), all patients with stage I GCT who experienced recurrence on AS were selected. Clinicodemographic information including recurrence pattern (tumor marker (TM), imaging, physical exam (PE), or a combination of these) were collected. Bifurcation of the common iliac arteries was defined as the anatomic landmark between CT abdomen and pelvis. The location of recurrent nodal disease was determined accordingly. Results: A total of 270 patients were included. 122(45%) patients had non-seminomatous GCT (NSGCT). 17(6%) patients had history of cryptorchidism and 38 (14%) had history of scrotal/inguinal surgery. The median time to recurrence for seminoma and NSGCT was 16 months (IQR 8–27) and 6 months (IQR 4–13), respectively. The most common method for detecting recurrence was imaging-only (49%) followed by combination of TM and imaging (43%). A total of 43/270(16%) patients had pelvic/inguinal nodal recurrence (PNR). Prior hernia repair was significantly higher in patients with pelvic/inguinal nodal disease compared to their counterparts (19%vs2.5%;p=0.01). PNR was detectable only by imaging in 16/270(6%) patients. However, in 11/16(69%) patients, PNRe was either visible on CT abdomen cuts or there was simultaneous retroperitoneal recurrence. Overall, only 5/270(1.8%) patients (4 seminoma, 1 NSGCT) had PNR only detectable on CT pelvis. Conclusions: CT abdomen only, chest imaging, TM and PE detect majority of recurrences in stage I GCT and CT pelvis could be safely omitted during AS. Future modification in AS protocols of stage I GCT may be warranted.[Table: see text]

Purpose After chemotherapy, approximately 50% of patients with metastatic testicular germ cell tumors (GCTs) who undergo retroperitoneal lymph node dissections (RPNLDs) for residual masses have fibrosis. Radiomics uses image processing techniques to extract quantitative textures/features from regions of interest (ROIs) to train a classifier that predicts outcomes. We hypothesized that radiomics would identify patients with a high likelihood of fibrosis who may avoid RPLND. Patients and Methods Patients with GCT who had an RPLND for nodal masses > 1 cm after first-line platinum chemotherapy were included. Preoperative contrast-enhanced axial computed tomography images of retroperitoneal ROIs were manually contoured. Radiomics features (n = 153) were used to train a radial basis function support vector machine classifier to discriminate between viable GCT/mature teratoma versus fibrosis. A nested 10-fold cross-validation protocol was used to determine classifier accuracy. Clinical variables/restricted size criteria were used to optimize the classifier. Results Seventy-seven patients with 102 ROIs were analyzed (GCT, 21; teratoma, 41; fibrosis, 40). The discriminative accuracy of radiomics to identify GCT/teratoma versus fibrosis was 72 ± 2.2% (area under the curve [AUC], 0.74 ± 0.028); sensitivity was 56.2 ± 15.0%, and specificity was 81.9 ± 9.0% ( P = .001). No major predictive differences were identified when data were restricted by varying maximal axial diameters (AUC range, 0.58 ± 0.05 to 0.74 ± 0.03). The prediction algorithm using clinical variables alone identified an AUC of 0.76. When these variables were added to the radiomics signature, the best performing classifier was identified when axial masses were limited to diameter < 2 cm (accuracy, 88.2 ± 4.4; AUC, 0.80 ± 0.05; P = .02). Conclusion A predictive radiomics algorithm had a discriminative accuracy of 72% that improved to 88% when combined with clinical predictors. Additional independent validation is required to assess whether radiomics allows patients with a high predicted likelihood of fibrosis to avoid RPLND.

To correlate the findings on 3T multiparametric prostate MRI using PIRADS version 2 with prostate biopsy results as the standard of reference. 134 consecutive treatment naive patients (mean age 64 years, range 41–82 years) underwent MRI-directed prostate biopsy. MRI–TRUS fusion biopsy was used for 77 (77/134 = 57.5%) patients, cognitive fusion for 51 (51/134 = 38.0%) patients, and 6 patients (6/134 = 4.5%) without a target nodule had systematic biopsy only. Out of the 1676 biopsy sites, 237 (237/1676 = 14.1%) were positive on MRI for a PIRADS 3, 4, or 5 nodule. Fifty-eight (58/134, 43.3%) patients had clinically significant prostate cancer (csPCa). The findings on MRI using PIRADS version 2 were correlated with the biopsy results. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of PIRADS ≥ 3 for csPCa were 89%, 76.5%, 89.7%, 31.7%, and 98.4%, respectively. The detection rates of csPCa for PIRADS 3, 4, and 5 nodules were 6.1% (4/66), 33.3% (42/126), and 64.4% (29/45), respectively. MRI did not identify a nodule in 23/1676 (1.4%) biopsy sites that contained csPCa. The MRI reader, biopsy operator, method of fusion biopsy, and zonal location of prostate nodule did not significantly affect the odds of having a biopsy result positive for csPCa. PIRADS ≥ 3 had high specificity and high negative predictive value for csPCa using biopsy results as the standard of reference. The presence of csPCa from a biopsy site was highly unlikely in the absence of a corresponding PIRADS ≥ 3 nodule.

Karl Rahner’s ecclesial theology remains relevant for ecumenical work and specifically for the ecumenically thorny questions about papal authority and the infallibility doctrine. Rahner’s approach offers insight for unifying Christian churches in three ways: 1. prioritizing the papal office’s unifying role; 2. interpreting the doctrine of infallibility within an incarnate ecclesiology; and 3. contextualizing papal authority within a theology of communion and a subsidiarity administrative model. With this approach, infallibility is framed as a matter of doctrine and order, but a doctrine and order rooted in and reflecting the ‘sensus fidelium’. The pope is the ‘concrete guarantor of the unity of the church in truth and love’ 1 and not an absolute monarch. Rahner’s call for ecumenical reforms serves the mission of the whole church – the sacrament of the incarnate God – on the personal, parish, diocese, regional, and universal levels. Many monarchical symbols of the papacy have been retired in recent years with the papacy of Francis, marking a moment ripe for Rahner’s approach. The article concludes with a reflection upon how Francis’ ministry reveals a commitment to communion theology of the Second Vatican Council and the subsidiarity principle that embodies Rahner’s epistemological tolerance.

Background Patients on surveillance for clinical stage I (CSI) testicular cancer are counseled regarding their baseline risk of relapse. The conditional risk of relapse (cRR), which provides prognostic information on patients who have survived for a period of time without relapse, have not been determined for CSI testicular cancer. Objective To determine cRR in CSI testicular cancer. Design, setting, and participants We reviewed 1239 patients with CSI testicular cancer managed with surveillance at a tertiary academic centre between 1980 and 2014. Outcome measurements and statistical analysis cRR estimates were calculated using the Kaplan-Meier method. We stratified patients according to validated risk factors for relapse. We used linear regression to determine cRR trends over time. Results and limitations At orchiectomy, the risk of relapse within 5 yr was 42.4%, 17.3%, 20.3%, and 12.2% among patients with high-risk nonseminomatous germ cell tumor (NSGCT), low-risk NSGCT, seminoma with tumor size ≥3cm, and seminoma with tumor size Conclusions After 2 yr, the risk of relapse on surveillance for CSI testicular cancer is very low. Consideration should be given to adapting surveillance protocols to individualized risk of relapse based on cRR as opposed to static protocols based on baseline factors. This strategy could reduce the intensity of follow-up for the majority of patients. Patient summary Our study is the first to provide data on the future risk of relapse during surveillance for clinical stage I testicular cancer, given a patient has been without relapse for a specified period of time.

The objective of our study was to determine whether small (4 cm) solid renal cell carcinomas (RCCs) enhance on CT below the published enhancement thresholds.For this retrospective study, we reviewed CT examinations of patients with pathologically characterized small solid renal masses. Patients with lipid-rich angiomyolipomas were excluded. The study included consecutive patients who had pathologically characterized small (4 cm) renal masses and had undergone CT during the un-enhanced phase and nephrographic phase (NP). Most CT examinations also included imaging during the corticomedullary phase (CMP); four patients did not have CMP images. The CT examinations were performed on a 64-MDCT scanner. Similar-sized ROIs were placed on each lesion on unenhanced and enhanced images and enhancement (in Hounsfield units) was calculated. Masses were considered solid with a threshold enhancement greater than either 15 or 20 HU.There were 137 masses in 137 patients, 90 men and 47 women (age range, 21-91 years; median age, 65 years). The renal masses were 1.0-3.9 cm (median, 2.4 cm). Of the 137 masses, 117 (85.4%) were malignant and 20 (14.6%) were benign. One malignant mass and three benign masses did not have CMP images. Twenty of the 116 (17.2%) renal cell carcinomas (RCCs) did not reach the 15-HU threshold enhancement on CMP images, nine of 117 masses (7.7%) did not reach the 15-HU enhancement threshold on NP images, and four of 117 masses (3.4%) did not reach the 15-HU enhancement threshold on both CMP and NP images. The numbers of masses that did not reach the 20-HU enhancement threshold were 24 of 116 masses (20.7%) on CMP images, 14 of 117 masses (11.9%) on NP images, and 11 of 117 masses (9.4%) on both CMP and NP images. Depending on the phase or enhancement threshold, 13.6-59.1% of papillary RCCs did not reach the enhancement threshold.A minority of small RCCs do not reach either a 15- or 20-HU enhancement threshold and might be misinterpreted as a hyperattenuating cyst. Most RCCs below these enhancement thresholds are papillary RCC.

Conditions of scarcity impact healthcare services for cancer patients. This is the unpleasant reality for nations, local governments, hospitals, and even individual doctors. This means that medical services judged by objective standards as potentially effective by medical professionals are limited because of financial or access scarcity. With this situation of scarcity as premise, one must raise the ethical question of how to deal with scarcity while respecting fundamental principles of human dignity and human rights. This chapter focuses on the German healthcare context where dignity and rights form the basis and framework for medical ethics. Accordingly, in Germany, rationing medical services for life-threatening diseases has been traditionally and appropriately criticized and prohibited. Granting a situation of scarcity, however, some prioritization becomes increasingly necessary. Thus, there is present need for careful ethical analysis of non-emergency regulatory prioritization principles and protocols. Above all, analysis and conclusions must preserve and foster society's deepest moral commitments.

Conditions of scarcity impact healthcare services for cancer patients. This is the unpleasant reality for nations, local governments, hospitals, and even individual doctors. This means that medical services judged by objective standards as potentially effective by medical professionals are limited because of financial or access scarcity. With this situation of scarcity as premise, one must raise the ethical question of how to deal with scarcity while respecting fundamental principles of human dignity and human rights. This chapter focuses on the German healthcare context where dignity and rights form the basis and framework for medical ethics. Accordingly, in Germany, rationing medical services for life-threatening diseases has been traditionally and appropriately criticized and prohibited. Granting a situation of scarcity, however, some prioritization becomes increasingly necessary. Thus, there is present need for careful ethical analysis of non-emergency regulatory prioritization principles and protocols. Above all, analysis and conclusions must preserve and foster society’s deepest moral commitments.

Retroperitoneal lymph node dissection is recommended for residual masses greater than 1 cm after chemotherapy of nonseminomatous germ cell tumors. Currently there is no reliable predictor of post-chemotherapy retroperitoneal lymph node dissection histology. Up to 50% of patients harbor necrosis/fibrosis only so that a potentially morbid surgery has limited therapeutic value. In this study we evaluated the ability of defined serum miRNAs to predict residual viable nonseminomatous germ cell tumors after chemotherapy.Levels of serum miRNA, including miR-371a-3p, miR-373-3p and miR-367-3p, were measured using the ampTSmiR (amplification targeted serum miRNA) test in 82 patients, including 39 in cohort 1 and 43 in cohort 2, who were treated with orchiectomy, chemotherapy and post-chemotherapy retroperitoneal lymph node dissection. miRNA levels were compared to clinical characteristics and serum tumor markers, and correlated with the presence of viable germ cell tumor vs fibrosis/necrosis and teratoma. ROC analysis was done to determine miRNA discriminative capacity.miRNA levels were significantly associated with disease extent at chemotherapy and they decreased significantly after chemotherapy. Conventional serum tumor marker levels were uninformative after chemotherapy. However, after chemotherapy miRNA levels remained elevated in patients harboring viable germ cell tumor in post-chemotherapy retroperitoneal lymph node dissection specimens. miR-371a-3p demonstrated the highest discriminative capacity for viable germ cell tumors (AUC 0.874, 95% CI 0.774-0.974, p0.0001). Using an adapted hypothetical cutoff of 3 cm or less for surgical intervention miR-371a-3p correctly stratified all patients with viable residual retroperitoneal germ cell tumors with 100% sensitivity (p = 0.02).Our study demonstrates for the first time the potential value of miR-371a-3p to predict viable germ cell tumors in residual masses after chemotherapy. Prospective studies are required to confirm clinical usefulness.

Testicular seminoma most commonly affects young men and is associated with favourable prognosis. Various followup schedules and imaging protocols for testicular seminoma have been described without overall consensus. We reviewed the literature together with our experience at the Princess Margaret Cancer Centre and present an evidence-based followup approach for patients with stage I and II seminoma.

Purpose Cisplatin-based chemotherapy, a mainstay of treatment for disseminated germ cell tumors (GCTs), is associated with venous thromboembolism (VTE). Many patients with disseminated GCTs have large retroperitoneal lymph node (RPLN) metastases that may cause venous stasis and increase the risk of VTE development. We hypothesized that there was an association between large RPLN and chemotherapy-associated VTE risk. Patients and Methods The training cohort was composed of patients with disseminated GCT receiving first-line chemotherapy at Princess Margaret Cancer Centre between January 2000 and December 2010. Large RPLN was defined as more than 5 cm in maximal axial diameter. The predictive and discriminatory accuracies of a model using large RPLN in predicting VTE were compared with high-risk Khorana score (≥ 3) using logistic regression and area under receiver operator characteristic curves (AUROCs). The model was externally validated in a cohort of patients treated at the London Health Sciences Centre. Results The training cohort comprised 216 patients, 21 (10%) of whom developed VTE during chemotherapy. VTE was associated with large RPLN (odds ratio [OR], 5.26; P = .001), high-risk Khorana score (OR, 11.8; P < .001), intermediate-/poor-risk disease (OR, 3.76; P = .005), and hospitalization during chemotherapy (OR, 4.24; P = .002). Large RPLN showed higher discriminatory accuracy than high-risk Khorana score (AUROC, 0.71 v 0.67, respectively). Superior discriminatory accuracy of large RPLN over high-risk Khorana score was validated in the London cohort (AUROC, 0.61 v 0.57, respectively). Conclusion Large RPLN is associated with VTE in patients with disseminated GCT and provides higher discriminatory accuracy than high-risk Khorana score. Results should be validated in larger, prospective studies. Prophylactic anticoagulation may be considered in high-risk patients.

Category: Ankle Arthritis Introduction/Purpose: Determining the etiology of pain after total ankle replacement (TAR) often serves as a diagnostic dilemma for many surgeons, particularly in the setting of normal appearing radiographs. Single photon emission computed tomography (SPECT CT) has been identified as a potentially useful tool to evaluate pain after TAR. However, prior research has been limited by a lack of comparison to clinical findings as well as comparison to other imaging modalities. Our study aims to add to the current understanding of the role of SPECT CT as a diagnostic tool in TAR. It is our hypothesis that SPECT CT would be predictive of clinical and intraoperative findings in patients with pain after TAR. Methods: A retrospective review was undertaken of SPECT CT imaging performed at our institution for the evaluation of painful TAR from January 2014 to November 2018. There were 35 patients identified during this time period who underwent SPECT CT to evaluate pain after TAR. The average length of time from index surgery to SPECT CT was 17.2 months. Of this cohort, 18 patients also had an MRI during the same time frame and images were available for comparison. Findings on the imaging studies were compared to clinical findings as documented in the medical record, as well as intraoperative findings at the time of revision surgery when one was performed. SPECT CT results, as well as MRI results when available, were evaluated for their consistency with documented clinical and intraoperative findings. Results: Of the 35 patients, 91.4% (32/35) had SPECT CT results that were consistent with clinical findings. Amongst the diagnoses for which SPECT CT was useful in this cohort, loosening (12/32) and impingement (10/32) were most common. Other diagnoses included malalignment (4/32), cyst formation (2/32), subtalar arthritis (2/32), and infection (2/32). In our cohort, 25 patients underwent revision surgery, and SPECT CT imaging was consistent with ultimate intraoperative findings in 24 (96.0%) cases. Procedures performed were revision for aseptic loosening (11/25), gutter debridement (5/25), revision for malalignment (2/25), hindfoot reconstruction (2/25), implant removal for infection (2/25), cyst grafting, subtalar arthrodesis, and conversion to ankle arthrodesis. In the 18 patients who also underwent MRI, these results were consistent with clinical findings 38.9% (7/18) of the time. Conclusion: In this cohort, there was a high consistency between SPECT CT results and documented clinical diagnoses. Additionally, in those patients who ultimately underwent revision surgery, SPECT CT demonstrated high consistency with intraoperative findings. When compared to MRI, SPECT CT proved more useful in helping to establish a diagnosis for pain after TAR in our cohort. Our series serves to highlight the utility of SPECT CT as an additional tool in evaluating the painful TAR. Further investigation into the interpretation of SPECT CT after TAR, including changes in physiologic postoperative uptake that occur over time, is warranted.

523 Background: Bilateral testicular germ cell tumours (BTC) form a small minority of testicular cancer and detailed management data are sparse. Methods: Bilateral testicular cancer (BTC) patients managed at a single cancer centre were retrospectively analyzed. Synchronous BTC was defined as uni+contralateral presentation within 3 months. Patient characteristics, treatment and outcomes were collected. Kaplan-Meier method was used to calculate the overall survival (OS) and relapse-free survival (RFS). Results: Between Jan 1971 to Jun 2018, 118 pts were included. Nine patients (7.6%) had cryptorchidism. Twenty-two patients (18.6%) had synchronous BTC at median age of 30(21-54) years, 11 presented with concordant histology (10-seminoma). Median follow-up time was 96(1-220) months. Two of 14 patients (14%) with stage I disease on surveillance had retroperitoneal nodal recurrence, other 3 (21%) had testicular recurrence after partial orchiectomy alone. No recurrence occurred for 8 stage II/III patients (36%) who received stage-appropriate treatment. All patients were alive without disease at last follow-up. For metachronous BTC, the median age was 27(16-68) and 37(19-78) years for first and second diagnosis, respectively. The median time interval was 88 (8-352) months, with shorter interval when second primary was non-seminoma, median 69 vs. 92 months. Concordant histology was present in 58 (38-seminoma) patients and discordant in 38 patients. There were 66, 23, 7 and 84, 9, 3 patients with stage I, II, III disease for first and second testicular cancer (TC), respectively. For all stage I disease, 69% of non-seminoma (n = 33) and 79% of seminoma (n = 81) were on surveillance, of whom the crude relapse rate was 15%. The median follow-up time after second diagnosis was 87 months. In all, 35 patients (30%) with recurrence except 1 were successfully salvaged. The 10-year OS and RFS for whole cohort was 99% and 69.8%, respectively. Conclusions: In our series, seminoma was the more common pathology, and management based on pathology and stage yielded excellent outcomes regardless of prior therapy. Metachronous BTC may occur at extremely long time intervals such that longer follow-up is needed to capture the majority of contralateral primary TC.

The basic human experience of the atrocities in the first half of the 20th century has significantly strengthened the recognition of human dignity and human rights for all born people at the political level. Therefore, the Charter of the United Nations in 1945 and its Universal Declaration of Human Rights of 1948, Article 1 affirms: 'All human beings are born free and equal in dignity and rights'. This article provides an ethical justification of why we in this political consensus should not waver, and why we should grant the right to life to all born human infants. Moreover, there is an ethical justification to granting the right to life even to unborn human beings, who already bear a human face.

Aims To identify the characteristics and outcomes associated with late relapse in stage I seminoma. Materials and methods A retrospective review was carried out of all patients with stage I seminoma managed at our institution between 1981 and 2011. Data were obtained from a prospectively maintained database. Late relapse was defined as tumour recurrence > 2 years after orchiectomy. Results Overall, 1060 stage I seminoma patients were managed with active surveillance ( n =766) or adjuvant radiotherapy ( n =294). At a median follow-up of 10.6 years (range 1.2–30), 142 patients relapsed at a median (range) of 14 (3–129) months; 128 on active surveillance and 14 after adjuvant radiotherapy. The late relapse rate for the active surveillance and adjuvant radiotherapy groups was 4% and 1%, respectively. There was no specific clinicopathological factor associated with late relapse. Isolated para-aortic node(s) was the most common relapse site in active surveillance patients either in late (88%) or early relapse (82%). Among the active surveillance group, no patients with late relapse subsequently developed a second relapse after either salvage radiotherapy ( n =25) or chemotherapy ( n =6), whereas in early relapse patients a second relapse was reported in seven (10%) of 72 patients treated with salvage radiotherapy and one (4%) of 23 patients who received chemotherapy; all second relapses were subsequently salvaged with chemotherapy. No patient in the adjuvant radiotherapy group developed a second relapse after salvage chemotherapy ( n =10) or inguinal radiotherapy/surgery ( n =4). Of seven deaths, only one was related to seminoma. Among active surveillance patients, the 10 year overall survival for late and early relapse groups were 100% and 96% ( P = 0.2), whereas the 10 year cancer-specific survival rates were 100% and 99% ( P = 0.3), respectively. Conclusions In stage I seminoma, the extent and pattern of late relapse is similar to that for early relapse. For active surveillance patients, selective use of salvage radiotherapy/chemotherapy for relapse results in excellent outcomes regardless of the timing of relapse, whereas salvage radiotherapy for late relapse seems to be associated with a minimal risk of second relapse.

The following discussion uses these three brief case studies to illustrate first the inadequacy of classic bioethical approaches and the basic reasons why approaches that rely on moralistic rules, shaming, and ethics as the setting of limiting rules are unable to efficiently guide medicine in avoiding the dilemmas of the cases. The paper then examines how structural misalignments and institutional incentives are relevant for medical ethics. Finally, the paper offers an argument for an ordonomic approach for medical ethics analogous to the ordonomic approach in business ethics (Pies et al. 2009).

Regenerative medicine is the scientific approach to medical treatment by means of replacing, regenerating, or engineering human tissue. RM goals present no inherent ethical difficulty and this paper addresses legal and ethical issues presented by potential RM methods. These methods include the creation and use of artificial gametes and tissues for organ replacement using various genetic technologies.

An important mission for the country is achieving sustainability while strengthening the middle class. American leadership and innovation can play a critical role in defining the interconnectedness of our economy and environment—and in unlocking, harnessing, and advancing green technologies. The State of Maryland has launched a Green Jobs Initiative focused on attracting green businesses, working with existing businesses to adopt sustainable practices, promoting clean energy research and use, and training the work force for ne, green-collar jobs.

OBJECTIVE: Universal screening for interpersonal violence is recommended despite a lack of confirmed efficacy. We hypothesized that the detection of violence via universal screening would result in high intervention rates for victims. METHODS: Women aged 18-65 years presenting to an emergency department were screened using a standard protocol. Medical and social work records were reviewed for positively screened patients. Outcomes included whether victims received counseling/referral services. Secondary outcomes were the documentation of services offered and safety assessment performed. RESULTS: A total of 1732 patients were evaluated; 615 (35.5%) responded positively to at least one query. Patients had a mean age of 34.7+/-12 years, 79% were non-white, 19% were married, and 76% had completed high school. Twenty-five out of 606 victims (4%) had documentation of violence. Residents were more likely than faculty or nurses to document domestic violence [3.3% (95% confidence interval 1.8-4.8%) versus 2.1 (0.9-3.4) versus 0.7 (0.0-1.4)]. The documentation of police contact, suicide/homicide risk, weapon presence, safety assessment and outside resource referrals occurred in less than 2% of charts. Only two victims were referred to social work (0.3%; 0-0.9%). CONCLUSION: Even in an institution with a heavy emphasis and training on interpersonal violence and alternative mechanisms for universal screening we could not prove that the identification of victims resulted in counseling/referral being offered in the emergency department. Language: en

4559 Background: After chemotherapy, > 50% of patients (pts) with metastatic testicular GCT who undergo retroperitoneal lymph node dissection (RPNLD) for residual masses are found to have fibrosis (F) alone on pathological examination. To minimize overtreatment, better prediction algorithms are needed to identify pts with F who can avoid RPLND. Radiomics uses image processing techniques to extract quantitative textures/features from tumor regions of interest (ROI) to train a classifier that predicts pathological findings. We hypothesized that radiomics may identify pts with a high predicted likelihood of F who may avoid RPLND. Methods: Pts with GCT who had an RPLND for nodal masses > 1cm after first line platinum chemotherapy were included. Preoperative contrast enhanced axial CT images of retroperitoneal ROI were manually contoured. 153 radiomics features trained a radial basis function support vector machine classifier to discriminate between viable GCT /Mature Teratoma (T) vs F. Nested ten-fold cross-validation protocol was employed to determine classifier accuracy. Clinical variables and restricted size criteria were used to optimize the classifier. Results: A total of 82 pts with 102 ROI were analyzed (GCT: 21; T: 41; F: 40). The discriminative accuracy of radiomics to identify GCT/T vs F was 72%(±2.2)(AUC: 0.74 (±0.028); positive predictive value: 67% (48-92%); negative predictive value: 74% (62-84%)(p = 0.001)). No major predictive differences were identified when data was restricted by varying maximal axial diameters (AUC range: 0.58(±0.05) - 0.74(±0.03)). Prediction algorithm using clinical variables alone identified an AUC of 0.71 (±0.15). When these variables were added to the radiomic signature, the best performing classifier was identified when axial tumors were limited to diameter < 2cm (accuracy: 88.2 (±4.4); AUC: 0.80 (±0.05)(p = 0.02)). Conclusions: A predictive radiomics algorithm had an overall discriminative accuracy of 72% that improved to 88% when combined with clinical details. Further independent validation is required to assess whether radiomics, in conjunction with standard clinical predictors, may allow pts with a high predicted likelihood of F to avoid RPLND.

We have read with great interest the article by Litie`reet al. ‘The components of progression as explanatoryvariables for overall survival in the Response EvaluationCriteria in Solid Tumours 1.1 database’ publishedrecently in the European Journal of Cancer [1]. We wereintrigued by the sub-categorisation of progressive dis-ease into (i) progression of targeted lesions; (ii) occur-rence of a new lesion and (iii) non-targeted progressivedisease and the potential implications of these on clinicalpractice and research.Response Evaluation Criteria in Solid Tumours(RECIST) were designed to provide an objective, uni-form and reliable method to reflect changes in tumourburden in clinical trials between international institu-tions [2–4]. Non-target lesions by definition are not eas-ily quantifiable and are said to be a qualitative measure.Progression based on non-target lesions in the setting ofpatients with baseline measurable disease was expectedto be a rare event but as demonstrated by Litie`reet al., is much more common than first thought [1].Intheir series, non-target lesion progression occurred in25%, 27% and 34% of patients with breast, lung andcolorectal cancer respectively [1].By RECIST 1.1, to achieve unequivocal progressionof a non-target lesion there must be: ‘an overall levelof substantial worsening in non-target disease that isof a magnitude that even in the presence of stable dis-ease or partial response of target lesions the treatingphysician would feel it important to change therapy’[3]. Progression in this setting has to be ‘unequivocal’but who defines what is ‘unequivocal’ and how does thisequate to objective assessments in international trials? Ifa quarter of patients may be removed from trials basedon these criteria as suggested by Litie`re et al. this needsbetter clarification particularly as these rates may behigher in other disease sites such as ovarian cancer,given the pattern of disease.In this setting, how do we ensure uniform assessmentacross sites with the current definition that creates a win-dow for bias? As benefits in trials become smaller, thesubjectivity of this evaluation may have a significantimpact on the overall study result. Close interaction withthe radiologist and clinician can help this decision pro-cess. In addition how can unequivocal progression ofnon-targeted lesions be defined in the setting of a centralreview? Central review is designed to be blinded to clin-ical information in order to standardise trial results.