International Collaborative Study Research Articles

Ki-67 immunoexpression and radiological assessment of necrosis improves accuracy of conventional and modified core biopsy systems in predicting the final grade assigned to adult-soft tissue sarcomas. An international collaborative study

Based on the French Federation Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, this study assesses the accuracy of conventional and modified core biopsy (CB) systems in predicting the final grade (low vs high) assigned to the resected specimen. Substituting Ki-67 immunoexpression for mitotic count, and radiological for histological assessment of necrosis, we used two modified FNCLCC CB grading systems: (1) Ki-67 immunoexpression alone, and (2) Ki-67 plus radiological assessment of necrosis. We graded 199 soft tissue sarcomas (STS) from nine centers, and compared the results for the conventional (obtained from local histopathology reports) and modified CB systems with the final FNCLCC grading of the corresponding resected specimens. Due to insufficient sample quality or lack of available radiologic data, five cases were not evaluated for Ki67 or radiological assessment of necrosis. The conventional FNCLCC CB grading system accurately identified 109 of the 130 high-grade cases (83.8%). The CB grading matched the final FNCLCC grading (low vs high) in 175 (87.9%) of the 199 resected tumors; overestimating the final grade in three cases and underestimating in 21 cases. Modified system 1 (Ki-67) accurately identified 117 of the 130 high-grade cases (90.0%). The CB grading matched the final FNCLCC grading (low vs high) in 175 (89.7%) of the 195 evaluated cases; overestimating seven and underestimating 13 cases. Modified system 2 (Ki-67 plus radiological necrosis) accurately identified 120 of the 130 high-grade cases (92.3%). This last matched the final FNCLCC grading (low vs high) in 177 (91.2%) of the 194 evaluated cases; overestimating seven and underestimating 10 cases. Modified system 2 obtained highest area under ROC curves, although not statistically significant. Underestimated CB grades did not correlate with histological subtypes, although many of the discrepant cases were myxoid tumors (myxofibrosarcomas or myxoid liposarcomas), leiomyosarcomas or undifferentiated pleomorphic/spindle cell sarcomas. Using modified FNCLCC CB grading systems to replace conventional mitotic count and histologic assessment of necrosis may improve the distinction between low and high-grade STS on CB. Our study confirms that classifying grade 1 as low grade and grades 2 and 3 as high grade improves correlation between CB and final grade by up to 21%, irrespective of CB system used. A higher than expected Ki-67 score in a low-grade sarcoma diagnosed on CB should raise concern that a higher-grade component may not have been sampled. Furthermore, correlation of all clinicopathological and radiological findings at multidisciplinary meetings is essential to assess the histological grade on CB as accurately as possible.

Magnetic Resonance Imaging Correlates of Multiple Sclerosis Immunopathological Patterns.

Histology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I-III). In patterns I and II, a T-cell- and macrophage-associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers. We evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow-up MRIs in relation to their histopathologically classified immunopathological patterns (n=161 subjects) and lesion edge features (n=112). A strong association of a ringlike enhancement and a hypointense T2-weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients. We provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021;90:440-454.

Are Absolute Monocyte Count and The Lymphocyte-Monocyte Ratio (LMR) Valid Prognostic Factors In Classical Hodgkin Lymphoma? An Evaluation Based On Data From 1079 Patients

IntroductionThere is an increasing amount of data showing that both host immunity and tumor microenvironment play an essential role in determining the clinical course in patients with Hodgkin lymphoma (HL) and may also influence their response to therapy. Some investigators have considered the absolute lymphocyte count (ALC) as a surrogate bio-marker of tumor-infiltrating lymphocytes reflecting systemic host immunity, while the absolute monocyte count (AMC) is regarded as a surrogate bio-marker of tumor-associated macrophages reflecting the tumor microenvironment. For many years lymphopenia has been considered as a negative factor predicting poor outcome in HL. Recently monocytosis and the lymphocyte-monocyte ratio (LMR= ALC/AMC), which combines these two surrogate bio-markers, have also been shown to be useful prognostic parameters in HL, particularly in terms of progression free survival (PFS). AimsThe aim of the present study was to verify whether AMC and LMR are indeed valid prognostic parameters in HL, utilizing a large cohort of patients with the disease. Materials and MethodsWe collected data from 1079 patients with classical Hodgkin's lymphoma (cHL) enrolled in different clinical trials of “Gruppo Italiano Studio Linfomi (GISL)” during 1988-2007. Previously we had evaluated a database of 371 patients with cHL and examined different AMC and LMR cut-off levels using the maximum log rank test and c-Harell (area under the curve). We identified AMC of 600/mm3 and LMR of 3.5, as optimal cut-off values. ResultsPatients in our current study had the following characteristics: median age 32 years (range 17-71), 51% males, 15% stage IV disease, 74% with International Prognostic Score (IPS) 0-2, 72% nodular sclerosis and 18% mixed cellularity; 43% were treated with ABVD and 29% with BEACOPP/BEACOPP-like regimens. Radiotherapy (RT) was administered to 66% of cases. Median follow-up was 6.8 years (range 0.1-19), and 5-years and 10-years overall survival (OS) was 89 and 83%, respectively; 5-years PFS was 79%. In an earlier evaluation the 10-years PFS for patients with AMC >600/mm3 and LMR <3.5 was significantly worse, compared to the group with AMC <600/mm3 and LMR >3.5 (p-value: 0.032 and 0.005). However now after applying the same cut-off values to the larger database, we found no statistical differences in PFS ,and both threshold values for AMC (600/mm3) and LMR (3.5) lost their prognostic power. Using the same statistical methods for the cohort of 1079 patients, we found different cut-off values for AMC and LMR, that were equally effective in splitting different survival patterns. For AMC the value of 750/mm3 (26% of patients with AMC >750/mm3), and for LMR a ratio of 1.5 (19% of patients with LMR <1.5) revealed a difference in PFS which was statistically significant (p-value 0.003 and 0.001, respectively), as shown in Figure 1. In multivariate analysis after adjusting by IPS, RT and type of chemotherapy regimen administered, AMC and LMR maintained their prognostic significance for PFS (HR 1.37, p 0.022 and 1.37, p 0.037). After interaction with IPS (Figure 2) LMR showed an uniform pattern within the two risk -groups (overall: HR=1.42, p 0.019; IPS 0-2: HR=1.34, p 0.181; IPS 3-7: HR=1.49, p 0.048). [Display omitted] [Display omitted] ConclusionsOur study of 1079 patients confirms that peripheral monocyte and lymphocyte counts have an important prognostic impact in cHL. The cut off-values we used, although different from those utilized previously, were able to distinguish patients with different PFS. The cut-offs reported in the literature vary according to the different authors and the various sets of patients examined. At present we feel there is still a clear need to finally establish definitive and more appropriate cut-off levels that can be used for all future studies. In order to achieve this goal, it is essential to study an even larger series of patients within the framework of an international collaborative study. Disclosures:No relevant conflicts of interest to declare.

Favorable outcome of NUTM1-rearranged infant and pediatric B cell precursor acute lymphoblastic leukemia in a collaborative international study

Favorable outcome of NUTM1-rearranged infant and pediatric B cell precursor acute lymphoblastic leukemia in a collaborative international study

The impact of the coronavirus (COVID-19) pandemic on individuals with gastrointestinal disorders: A protocol of an international collaborative study

ObjectiveThe COVID-19 pandemic has had a significant impact on mental health across the globe. People living with a chronic gastrointestinal (GI) disorder might be particularly at risk of mental health complications given higher rates of comorbid anxiety and depression compared to the healthy population. As GI disorders affect up to 40% of the population worldwide, this international collaborative study seeks to evaluate the extent of the impact of the COVID-19 pandemic on GI symptoms specifically and more generally on the well-being of those living with chronic GI conditions. MethodsA longitudinal survey with three time points (baseline, 6-month, and 12-month) will be conducted online. Adult participants with GI disorders from multiple countries will be recruited via patient associations, social media advertising, utilizing snowball sampling. Participants will be invited to complete a battery of questionnaires including demographic and health parameters, and measures of gastrointestinal symptoms, fear of COVID-19, perceived impact of COVID-19, illness perceptions, coping, depression, anxiety, stress, catastrophizing, and quality of life, using validated measures where available. Statistical analyses will include univariate descriptive models, multivariate models utilizing regression, mediation, and moderation, and latent growth models. ConclusionsThis project may present novel information to the field of psychogastroenterology and may provide crucial information regarding the areas of impact for individuals with GI disorders during and following the pandemic. Further, this information can guide healthcare providers and patient associations on how to target support related to the pandemic mental health sequelae for these patients.

Acute Liver Injury Among Pediatric Liver Transplantation Recipients With Coronavirus Disease 2019: An International Collaborative Study.

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic. The occurrence of acute liver injury (ALI) has been reported in liver transplant (LT) recipients; however, the findings on children remain controversial. This is the first extensive, worldwide report on the impact of COVID-19 on pediatric LT recipients. Our online survey reported 110 pediatric LT recipients with severe acute respiratory syndrome coronavirus 2 infection. Of these, 37 were symptomatic and 20 out of them (54%) had complicated COVID-19, which included ALI and acute liver graft rejection. No mortality was reported. Pediatric LT recipients who had undergone transplantation less than 6 months before contracting COVID-19 had a greater number of hospital admissions and a higher ALI frequency (P = 0.013 and P = 0.033, respectively) than those who had undergone transplantation more than 6 months prior. Our study found that COVID-19 cases among pediatric LT recipients demonstrated a high complication rate. We propose that these patients must be followed up strictly.

Burkitt lymphoma of the head and neck: An international collaborative study.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma with three variants (endemic, sporadic, and immunodeficiency-associated), presenting with specific epidemiological and clinical features. Burkitt lymphoma affects the head and neck region (BLHN) in approximately 10% of cases. The aim of this study was to undertake a comparative analysis of the clinicopathologic and immunohistochemical (IHC) features of BLHN diagnosed in patients from Africa, Guatemala, and Brazil. Cases diagnosed as BLHN were collected from the files of six oral pathology laboratory services (Brazil, South Africa, and Guatemala) and one Brazilian pediatric oncology hospital from 1986 to 2020. Clinicopathological and IHC data, and Epstein-Barr virus (EBV) status by in situ hybridization data for each case were reviewed and described. Of the 52 cases, BLHN was predominant in pediatric patients [43 (82.69%)] and males [43 (82.69%)], with a mean age of 11.26 ± 9.68 years (range, 1-39 years). Neck and cervical lymph nodes [14 (26.92%)], and involvement of both maxilla and mandible [8 (15.38%)], were the most common anatomical sites. Clinically, tumor/swelling [40 (31.25%)], cervical lymphadenopathy [14 (10.94%)], pain [12 (9.38%)], and bone destruction [12 (9.38%)] were frequent findings. All cases showed typical morphological characteristics of BL. IHC profiles included positivity for CD20 [52 (100%)], CD10 [38 (79.17%)], Bcl6 [29 (87.88%)], and c-Myc protein [18 (81.82%)]. EBV was positive in 18 cases (62.07%). The Ki-67 index ranged from 90 to 100%. The clinicopathological and EBV profile of BLHN in South African, Guatemalan, and Brazilian patients is similar.

A first WHO reference reagent for the detection of anti-human platelet antigen-15b.

Background and ObjectivesAlloantibodies to human platelet antigen‐15b (anti‐HPA‐15b) have been detected in mothers with foetal–neonatal alloimmune thrombocytopenia and in multiply transfused patients. Assays used to detect this antibody, which aids in disease diagnosis, can be unreliable and vary in sensitivity. The objective was to generate a stable, lyophilized anti‐HPA‐15b preparation and evaluate its suitability as a World Health Organization (WHO) reference reagent for use in the quality control of platelet alloantibody detection assays. Results from an international collaborative study to evaluate the preparation were used to assign a minimum potency at which laboratories can be expected to detect the antibody.Materials and MethodsRecalcified plasma containing anti‐HPA‐15b was aliquotted, lyophilized and coded 18/220. Twenty‐five laboratories in 16 countries tested doubling dilutions of the reconstituted material in glycoprotein‐specific assays such as the monoclonal antibody–specific immobilization of platelet antigen assay and reported the last positive (or endpoint) dilution.ResultsTwenty‐four laboratories (96%) detected antibodies with HPA‐15b specificity in preparation 18/220. Reported endpoint dilutions were normally distributed with a modal dilution of 1 in 16 and ranged from 1 in 2 to 1 in 128. Only two laboratories (8%) failed to detect anti‐HPA‐15b at 1 in 8 dilution.ConclusionsWhen diluted 1 in 8, most laboratories detected anti‐HPA‐15b in preparation 18/220 using HPA‐15bb platelets but not with HPA‐15aa platelets. The participants agreed this to be an appropriate dilution for assignment as the minimum potency. In October 2020, the WHO Expert Committee on Biological Standardization approved 18/220 as an International Reference Reagent.

Does general comorbidity impact the postoperative outcomes after surgery for large and giant petroclival meningiomas?

We assessed the role of the general condition of the patient in addition to usual anatomical reasoning to improve the prediction of personalized surgical risk for patients harboring a large and giant petroclival meningiomas. Single-center, retrospective observational study including adult patients surgically treated for a large and giant petroclival meningioma between January 2002 and October 2019 in a French tertiary neurosurgical skull-base center by one Neurosurgeon. Inclusion criteria were as follows: (1) histopathologically proven meningioma; (2) larger than 3cm in diameter; (3) located within the upper two-thirds of the clivus, the inferior petrosal sinus, or the petrous apex around the trigeminal incisura, medial to the trigeminal nerve. Clinical and radiological characteristics were gathered preoperatively including ASA score, the modified frailty index, and the Charlson comorbidity index. Post-operative severe neurological and non-neurological complications were collected. A total of 102 patients harboring a large and giant petroclival meningioma were included. The rate of postoperative death was 3.0% related to a congestive heart failure (n = 1), a surgical site hematoma (n = 1), and an ischemic stroke (n = 1). A severe neurological impairment was found in 12.8% and a severe non-neurological morbidity was found in 4.0%. The overall rate of severe morbidity and mortality was 15.7% after large and giant petroclival meningioma surgery. The presence of brainstem peri-tumoral edema (adjusted OR, 4.83 [95% CI 1.84-7.52], p = 0.028) was independently associated with a history of postoperative severe neurological morbidity. Male gender (adjusted OR, 7.42 [95% CI 1.05-49.77], p = 0.044), major cardiovascular morbidity (adjusted OR, 9.5 [95% CI 1.05-86.72], p = 0.045), and an ASA score ≥ 2 (adjusted OR, 11.09 [95% CI 1.46-92.98], p = 0.038) were independently associated with a history of postoperative severe non-neurological morbidity. A modified frailty index ≥ 1 (adjusted OR, 3.13 [95% CI 1.07-9.93], p = 0.047) and a low neurosurgical experience (adjusted OR, 5.38 [95% CI 1.38-20.97], p = 0.007) were independently associated with a history of postoperative overall morbidity and mortality. Pre-operative cranial nerve deficits (adjusted OR, 4.77 [95% CI 1.02-23.31], p = 0.024) and gross total resection (adjusted OR, 10.72 [95% CI 1.72-66.90], p = 0.022) were independently associated with postoperative new cranial nerve deficits. This study suggests to add scores assessing the patient general condition in daily practice to improve the selection of patients eligible for surgery. Collaborative international multicenter studies will be necessary to confirm these results and allow their implementation in clinical routine.

Ibero-American Endometriosis Patient Phenome: Demographics, Obstetric-Gynecologic Traits, and Symptomatology.

Background: An international collaborative study was conducted to determine the demographic and clinical profiles of Hispanic/Latinx endometriosis patients from Latin America and Spain using the Minimal Clinical Questionnaire developed by the World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonization Project (EPHect).Methods: This is a cross-sectional study to collect self-reported data on demographics, lifestyle, and endometriosis symptoms of Hispanic/Latinx endometriosis patients from April 2019 to February 2020. The EPHect Minimal Clinical Questionnaire (EPQ-M) was translated into Spanish. Comprehension and length of the translated survey were assessed by Spanish-speaking women. An electronic link was distributed via social media of endometriosis patient associations from 11 Latin American countries and Spain. Descriptive statistics (frequency, means and SD, percentages, and proportions) and correlations were conducted using SPSSv26.Results: The questionnaire was completed by 1,378 participants from 23 countries; 94.6% had self-reported diagnosis of endometriosis. Diagnostic delay was 6.6 years. Most participants had higher education, private health insurance, and were employed. The most common symptoms were back/leg pain (85.4%) and fatigue (80.7%). The mean number of children was 1.5; 34.4% had miscarriages; the mean length of infertility was 3.7 years; 47.2% reported pregnancy complications. The most common hormone treatment was oral contraceptives (47.0%). The most common comorbidities were migraines (24.1%), polycystic ovary syndrome (PCOS) (22.2%), and irritable bowel syndrome (21.1%). Most participants (97.0%) experienced pelvic pain during menses; for 78.7%, pain was severe; 86.4% reported dyspareunia. The mean age of dysmenorrhea onset was 16.2 years (SD ± 6.1). Hormone treatments were underutilized, while impact was substantial. Pain catastrophizing scores were significantly correlated with pain intensity (p < 0.001).Conclusion: This is the first comprehensive effort to generate a clinical–demographic profile of Hispanic/Latinx endometriosis patients. Differences in clinical presentation compared to other cohorts included higher prevalence and severity of dysmenorrhea and dyspareunia and high levels of pain catastrophizing. Though future studies are needed to dissect the impact of race and ethnicity on pain and impact, this profile is the first step to facilitate the recognition of risk factors and diagnostic features and promote improved clinical management of this patient population. The EPHect questionnaire is an efficient tool to capture data to allow comparisons across ethnicities and geographic regions and tackle disparities in endometriosis research.

Patients who will undergo elective inpatient surgery as a priority group to receive vaccination against SARS-CoV-2.

Patients who will undergo elective inpatient surgery as a priority group to receive vaccination against SARS-CoV-2.

EMBR-03. PINEOBLASTOMA: A POOLED OUTCOME STUDY OF NORTH AMERICAN AND AUSTRALIAN THERAPEUTIC DATA

BackgroundPineoblastoma (PB) is a rare embryonal brain tumour most often diagnosed in young children. To date, no clinical trials have been conducted specific to pediatric PB. Collaborative studies performed over the past 30 years have included PB in studies accruing for other embryonal tumours, primarily medulloblastoma (MB), but also including the entity formerly known as CNS-PNET and atypical teratoid rhabdoid tumors. Each of these studies have included only a small number of children with PB, making clinical features difficult to interpret and determinants of outcome difficult to ascertain. Patients and MethodsPublished centrally reviewed series with sufficient treatment and outcome data from North American and Australian cases were pooled. To investigate associations between variables, Fisher’s exact and Wilcoxon-Mann-Whitney tests, and Spearman correlations were used as appropriate. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used in survival analysis. ResultsWe describe a 30-year review of the reported clinical features of PB and a pooled centrally reviewed, cohort analysis of cases (n=178) from the Children’s Oncology Group (COG) (n=82) groups and several published, centrally reviewed institutional series (n=96). We find young children <3 years of age have a dramatically poorer outlook compared to older children (5-year OS 16.2% +/- 5.3% vs 67.3% +/- 5%) confirming new and novel approaches are needed in future clinical trials for this at risk group. Interestingly, male gender was predictive of worse outcome possibly suggestive of gender specific subgroup risks that needs validation in future studies. Assessment of radiation therapy is not possible as the vast majority of children under age three did not receive any form of radiation therapy. ConclusionGiven the relative scarcity of this tumor and the emerging data on subgroups of pineoblastoma, prospective, collaborative international studies will be vital to improving the long-term survival of these patients.

P0785 - Novel classification for upper tract urothelial carcinoma to better risk-stratify patients eligible for kidney sparing strategies: an international collaborative study

P0785 - Novel classification for upper tract urothelial carcinoma to better risk-stratify patients eligible for kidney sparing strategies: an international collaborative study

Characteristics and outcome of patients with low-/intermediate-risk acute promyelocytic leukemia treated with arsenic trioxide: an international collaborative study.

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide and all-trans retinoic acid. All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. The acute promyelocytic leukemia was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) of the patients were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after starting therapy. With a median follow-up of 1.99 years (95% confidence interval: 1.61-2.30 years) 1-year and 2-year overall survival rates were 97% (95% confidence interval: 94-100%) and 95% (95% confidence interval: 91-99%), respectively. Age above 70 years was associated with a significantly shorter overall survival (P<0.001) compared to that of younger patients. So far no relapses have been observed. Six patients (4%) died in complete remission at a median of 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of arsenic trioxide and all-trans retinoic acid therapy in the primary management of adults with low-/intermediate-risk acute promyelocytic leukemia in the real-life setting, irrespective of age.

Pretreatment Risk Stratification for Endoscopic Kidney-sparing Surgery in Upper Tract Urothelial Carcinoma: An International Collaborative Study

BackgroundSeveral groups have proposed features to identify low-risk patients who may benefit from endoscopic kidney-sparing surgery in upper tract urothelial carcinoma (UTUC). ObjectiveTo evaluate standard risk stratification features, develop an optimal model to identify ≥pT2/N+ stage at radical nephroureterectomy (RNU), and compare it with the existing unvalidated models. Design, setting, and participantsThis was a collaborative retrospective study that included 1214 patients who underwent ureterorenoscopy with biopsy followed by RNU for nonmetastatic UTUC between 2000 and 2017. Outcome measurements and statistical analysisWe performed multiple imputation of chained equations for missing data and multivariable logistic regression analysis with a stepwise selection algorithm to create the optimal predictive model. The area under the curve and a decision curve analysis were used to compare the models. Results and limitationsOverall, 659 (54.3%) and 555 (45.7%) patients had ≤pT1N0/Nx and ≥pT2/N+ disease, respectively. In the multivariable logistic regression analysis of our model, age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.0–1.03, p = 0.013), high-grade biopsy (OR 1.81, 95% CI 1.37–2.40, p < 0.001), biopsy cT1+ staging (OR 3.23, 95% CI 1.93–5.41, p < 0.001), preoperative hydronephrosis (OR 1.37 95% CI 1.04–1.80, p = 0.024), tumor size (OR 1.09, 95% CI 1.01–1.17, p = 0.029), invasion on imaging (OR 5.10, 95% CI 3.32–7.81, p < 0.001), and sessile architecture (OR 2.31, 95% CI 1.58–3.36, p < 0.001) were significantly associated with ≥pT2/pN+ disease. Compared with the existing models, our model had the highest performance accuracy (75% vs 66–71%) and an additional clinical net reduction (four per 100 patients). ConclusionsOur proposed risk-stratification model predicts the risk of harboring ≥pT2/N+ UTUC with reliable accuracy and a clinical net benefit outperforming the current risk-stratification models. Patient summaryWe developed a risk stratification model to better identify patients for endoscopic kidney-sparing surgery in upper tract urothelial carcinoma.

Novel prostate cancer susceptibility gene SP6 predisposes patients to aggressive disease

Prostate cancer (PrCa) is one of the most common cancers in men, but little is known about factors affecting its clinical outcomes. Genome-wide association studies have identified more than 170 germline susceptibility loci, but most of them are not associated with aggressive disease. We performed a genome-wide analysis of 185,478 SNPs in Finnish samples (2738 cases, 2400 controls) from the international Collaborative Oncological Gene-Environment Study (iCOGS) to find underlying PrCa risk variants. We identified a total of 21 common, low-penetrance susceptibility loci, including 10 novel variants independently associated with PrCa risk. Novel risk loci were located in the 8q24 (CASC8 rs16902147, OR 1.86, padj = 3.53 × 10−8 and rs58809953, OR 1.71, padj = 4.00 × 10−6; intergenic rs79012498, OR 1.81, padj = 4.26 × 10−8), 17q21 (SP6 rs2074187, OR 1.66, padj = 3.75 × 10−5), 11q13 (rs12795301, OR 1.42, padj = 2.89 × 10−5) and 8p21 (rs995432, OR 1.38, padj = 3.00 × 10−11) regions. Here, we describe SP6, a transcription factor gene, as a new, potentially high-risk gene for PrCa. The intronic variant rs2074187 in SP6 was associated not only with overall susceptibility to PrCa (OR 1.66) but also with a higher odds ratio for aggressive PrCa (OR 1.89) and lower odds for non-aggressive PrCa (OR 1.43). Furthermore, the new intergenic variant rs79012498 at 8q24 conferred risk for aggressive PrCa. Our findings highlighted the power of a population-stratified approach to identify novel, clinically actionable germline PrCa risk loci and strongly suggested SP6 as a new PrCa candidate gene that may be involved in the pathogenesis of PrCa.

Dermatología comunitaria en Uruguay y en el mundo

Community dermatology is a subspecialty that aims to bring dermatology to the community. Unlike what dermatological consultations in clinics involve, where patients personally consult a dermatologist, community dermatology allows the specialization to reach many individuals in a specific intervention, which can be educational or consist in the provision of healthcare.This study aims to summarize different actions that have been implemented in this field, both globally and regionally, focusing on activities that have been developed in our context. National awareness campaigns, international collaborative studies, even innovative workshops for rural schools. Details about work in community dermatology in Uruguay are described in the study.In a time when esthetic dermatology and state of the art drugs threaten to occupy all areas of dermatology worldwide, prevention actions and primary healthcare seem to be more relevant than ever.To conclude, community dermatology is a developing reality in our country with good prospects of continuing to grow, with the purpose of educating our population on basic care of the skin, as well as in highly prevalent pathologies.

Rural\u2013urban disparities in patient satisfaction with oral health care: a provincial survey

BackgroundIdentifying spatial variation in patient satisfaction is essential to improve the quality of care. Thus, the objective of this study was to investigate rural–urban disparities in patient satisfaction and to determine the factors that could influence satisfaction with oral health care.MethodsData from 1788 parents/caregivers of children who participated in the Quebec Ministry of Health clinical study were subject to secondary analysis. The Perneger model of patient satisfaction was used as the conceptual framework for the study. Satisfaction with oral health care was measured using the WHO-sponsored International Collaborative Study of Oral Health Outcomes (ICS-II). Explanatory variables included predisposing factors and enabling resources. Statistical analyses included descriptive statistics, as well as bivariate and linear regression models.ResultsIndividuals with higher income, dental insurance coverage, having a family dentist, reporting ease in finding a dentist, and having access to a private dental clinic were more satisfied with oral health care (p < 0.001). There were statistically significant differences between rural and urban Quebec residents in their ratings of patient satisfaction on four items, including dental office location (p = 0.013), dental equipment (p = 0.016), cost of dental treatment (p < 0.001), and cleanliness of dental office (p = 0.004), with greater satisfaction for urban dwellers. The multiple linear regression model showed that major determinants of patient satisfaction were being born in Canada, income ≥ 40,000$ CAD, having a family dentist, and having visited the dentist in the last year for regular checkups. However, ethnicity, having difficulty finding a dentist, and being in need of dental treatment negatively influenced patient satisfaction with oral health care.ConclusionsThese findings suggest that Quebec rural–urban disparity exists in patient satisfaction with care and that determinants of health influence this outcome. Intensive and powerful knowledge dissemination activities are needed to mobilize policymakers in implementing public health strategies to reduce this disparity.

Lag Time between Onset of First Symptom and Treatment of Retinoblastoma: An International Collaborative Study of 692 Patients from 10 Countries.

Simple SummaryThe authors aimed to determine the lag time between onset of symptoms and diagnosis of retinoblastoma in countries based on their national-income and analyse its effect on the outcomes. Based on analysis of 692 retinoblastoma patients from 11 treatment centres in 10 countries, there was a statistically significant difference in the lag time between onset of symptoms and diagnosis of retinoblastoma based on country income level. This difference in the lag time between different countries results in varied outcomes across patients. Shorter lag time results in better chances of eye and patient survival.Background: The relationship between lag time and outcomes in retinoblastoma (RB) is unclear. In this study, we aimed to study the effect of lag time between onset of symptoms and diagnosis of retinoblastoma (RB) in countries based on their national-income and analyse its effect on the outcomes. Methods: We performed a prospective study of 692 patients from 11 RB centres in 10 countries from 1 January 2019 to 31 December 2019. Results: The following factors were significantly different among different countries based on national-income level: age at diagnosis of RB (p = 0.001), distance from home to nearest primary healthcare centre (p = 0.03) and mean lag time between detection of first symptom to visit to RB treatment centre (p = 0.0007). After adjusting for country income, increased lag time between onset of symptoms and diagnosis of RB was associated with higher chances of an advanced tumour at presentation (p < 0.001), higher chances of high-risk histopathology features (p = 0.003), regional lymph node metastasis (p < 0.001), systemic metastasis (p < 0.001) and death (p < 0.001). Conclusions: There is a significant difference in the lag time between onset of signs and symptoms and referral to an RB treatment centre among countries based on national income resulting in significant differences in the presenting features and clinical outcomes.

The First WHO International Standard for Adalimumab: Dual Role in Bioactivity and Therapeutic Drug Monitoring.

The expanded availability of adalimumab products continues to widen patient access and reduce costs with substantial benefit to healthcare systems. However, the long-term success of these medicines is highly dependent on maintaining consistency in quality, safety and efficacy while minimizing any risk of divergence during life-cycle management. In recognition of this need and demand from global manufacturers, the World Health Organization (WHO) Expert Committee on Biological standardization established the WHO 1st International standard (IS) for Adalimumab (coded 17/236) in October 2019 with a defined unitage ascribed to each of the individual bioactivities evaluated in the study namely, TNF-α binding, TNF-α neutralization, complement dependent cytotoxicity and antibody-dependent cellular cytotoxicity. For development of the IS, two candidate standards were manufactured as per WHO recommendations. Analysis of extensive datasets generated by testing of a common set of samples including the candidate standards by multiple stakeholders including regulatory agencies using their own qualified assays in a large international collaborative study showed comparable biological activity for the tested candidates for the different activities. Use of a common standard significantly decreased the variability of bioassays and improved agreement in potency estimates. Data from this study clearly supports the utility of the IS as an important tool for assuring analytical assay performance, for bioassay calibration and validation, for identifying and controlling changes in bioactivity during life-cycle management and for global harmonization of adalimumab products. In addition, in a separate multi-center study which included involvement of hospital and clinical diagnostic laboratories, the suitability of the adalimumab IS for therapeutic drug monitoring assays was examined by analysis of data from testing of a common blind coded panel of adalimumab spiked serum samples representative of the clinical scenario along with the IS and in-house standards in diverse immunoassays/platforms. Both commercially available and in-house assays that are routinely used for assessing adalimumab trough levels were included. Excellent agreement in estimates for adalimumab content in the spiked samples was observed regardless of the standard or the method with inter-laboratory variability also similar regardless of the standard employed. This data, for the first time, provides support for the extended applicability of the IS in assays in use for therapeutic drug monitoring based on the mass content of the IS. The adalimumab IS, in fulfilling clinical demand, can help toward standardizing and harmonizing clinical monitoring assays for informed clinical decisions and/or personalized treatment strategies for better patient outcomes. Collectively, a significant role for the adalimumab IS in assuring the quality, safety and efficacy of adalimumab products globally is envisaged.