International Multicenter Collaboration Research Articles

DNA methylation episignature and comparative epigenomic profiling of HNRNPU-related neurodevelopmental disorder

PurposeHNRNPU haploinsufficiency is associated with developmental and epileptic encephalopathy 54. This neurodevelopmental disorder is characterized by developmental delay, intellectual disability, speech impairment, and early-onset epilepsy. We performed genome-wide DNA methylation (DNAm) analysis in a cohort of individuals to develop a diagnostic biomarker and gain functional insights into the molecular pathophysiology of HNRNPU-related disorder. MethodsDNAm profiles of individuals carrying pathogenic HNRNPU variants, identified through an international multicenter collaboration, were assessed using Infinium Methylation EPIC arrays. Statistical and functional correlation analyses were performed comparing the HNRNPU cohort with 56 previously reported DNAm episignatures. ResultsA robust and reproducible DNAm episignature and global DNAm profile were identified. Correlation analysis identified partial overlap and similarity of the global HNRNPU DNAm profile to several other rare disorders. ConclusionThis study demonstrates new evidence of a specific and sensitive DNAm episignature associated with pathogenic heterozygous HNRNPU variants, establishing its utility as a clinical biomarker for the expansion of the EpiSign diagnostic test.

SC121 - Perioperative complications after radical cystectomy for bladder cancer: an international multicenter collaboration

SC121 - Perioperative complications after radical cystectomy for bladder cancer: an international multicenter collaboration

Immediate radical cystectomy versus BCG immunotherapy for T1 high-grade non-muscle-invasive squamous bladder cancer: an international multi-centre collaboration.

To compare cancer-specific mortality (CSM) and overall mortality (OM) between immediate radical cystectomy (RC) and Bacillus Calmette-Guérin (BCG) immunotherapy for T1 squamous bladder cancer (BCa). We retrospectively analysed 188 T1 high-grade squamous BCa patients treated between 1998 and 2019 at fifteen tertiary referral centres. Median follow-up time was 36months (interquartile range: 19-76). The cumulative incidence and Kaplan-Meier curves were applied for CSM and OM, respectively, and compared with the Pepe-Mori and log-rank tests. Multivariable Cox models, adjusted for pathological findings at initial transurethral resection of bladder (TURB) specimen, were adopted to predict tumour recurrence and tumour progression after BCG immunotherapy. Immediate RC and conservative management were performed in 20% and 80% of patients, respectively. 5-year CSM and OM did not significantly differ between the two therapeutic strategies (Pepe-Mori test p = 0.052 and log-rank test p = 0.2, respectively). At multivariable Cox analyses, pure squamous cell carcinoma (SqCC) was an independent predictor of tumour progression (p = 0.04), while concomitant lympho-vascular invasion (LVI) was an independent predictor of both tumour recurrence and progression (p = 0.04) after BCG. Patients with neither pure SqCC nor LVI showed a significant benefit in 3-year recurrence-free survival and progression-free survival compared to individuals with pure SqCC or LVI (60% vs. 44%, p = 0.04 and 80% vs. 68%, p = 0.004, respectively). BCG could represent an effective treatment for T1 squamous BCa patients with neither pure SqCC nor LVI, while immediate RC should be preferred among T1 squamous BCa patients with pure SqCC or LVI at initial TURB specimen.

A0765 - Perioperative complications after radical cystectomy for bladder cancer: An international multicenter collaboration

A0765 - Perioperative complications after radical cystectomy for bladder cancer: An international multicenter collaboration

372. Comparing the Outcome of COVID-19 in Cancer and Non-Cancer Patients: an International Multicenter Study

BackgroundOur objective was to describe the clinical course, risk factors and outcomes of patients infected with COVID-19 around the globe comparing cancer to non-cancer patients.MethodsWe conducted a retrospective cohort study of COVID-19 confirmed cases through an international multicenter collaboration including 17 centers around the world including the United States of America, Brazil, Europe, Far East, Middle East and Australia from January to date. We evaluated the patients’ clinical characteristics, clinical course of the disease, hospitalization and outcome. Death was considered to be COVID-associated if it occurred within 30 days from the time of diagnosis.ResultsPreliminary data on 571 patients included 186 cancer patients and 385 non-cancer patients.Cancer patients were more likely to have COPD and received steroids but were less likely to have COVID-related symptoms compared to non-cancer patients (84% vs 97%, p< 0.0001). The rate of pneumonia with hypoxia, non-invasive ventilation and mechanical ventilation were similar in both groups. Despite the fact that hospital admissions were significantly higher in non-cancer patients (70% vs 56%, p< 0.001), promising antiviral and immune-related therapy including remdesivir, convalescent plasma and immunomodulators were more commonly used in cancer patients compared to non-cancer patients (P=0.04). Cancer patients had a higher COVID-associated mortality rate compared to non-cancer patients (20% vs 11%, p=0.006).ConclusionDespite the fact that cancer patients received more frequent antiviral and immune-related therapy, the mortality rate among cancer patients was significantly higher than non-cancer patients.Disclosures Roy F. Chemaly, MD, MPH, FACP, FIDSA, Chimerix (Consultant, Research Grant or Support)Clinigen (Consultant)Merck (Consultant, Research Grant or Support)Novartis (Research Grant or Support)Oxford Immunotec (Consultant, Research Grant or Support)Shire/Takeda (Research Grant or Support)Viracor (Research Grant or Support) Issam I. Raad, MD, Citius (Other Financial or Material Support, Ownership interest)Cook Medical (Grant/Research Support)Inventive Protocol (Other Financial or Material Support, Ownership interest)Novel Anti-Infective Technologies (Shareholder, Other Financial or Material Support, Ownership interest)

Surgical Management and Outcomes of Renal Tumors Arising from Horseshoe Kidneys: Results from an International Multicenter Collaboration

BackgroundDespite being the most frequent renal fusion anomaly, tumors arising from horseshoe kidneys (HSKs) are extremely rare and management guidance is lacking. ObjectiveTo evaluate the perioperative, oncological, and functional outcomes of surgically treated HSK tumors. Design, setting, and participantsA retrospective, multicenter cohort study of 43 HSK tumors in 40 patients was conducted, and technical description of the surgical approach has been provided. Surgical procedureSurgical resection of renal tumors arising from HSKs was performed either via open surgery or via minimally invasive surgery (MIS). MeasurementsWe analyzed patient and tumor characteristics as well as surgical technique, and functional and oncological outcomes. Results and limitationsEight patients were treated by MIS and 32 by open surgery. One patient (2.5%) experienced an intraoperative complication and 13 patients (32.5%) experienced postoperative complications, of which three (7.5%) were Clavien-Dindo ≥3 complications. Surgical margins were positive in two tumors (4.7%). The most frequent histology was clear-cell renal cell carcinoma (46.5%). The median follow-up was 51 (interquartile range [IQR] 17–73) mo. The 5-yr overall, cancer-specific, and recurrence-free survival rates were 81.2%, 86.8%, and 83.1%, respectively. The percent decreases in estimated glomerular filtration rate at discharge and the last follow-up were 15% (IQR 4–26%) and 17% (IQR 1–31%), respectively. Limitations include the cohort's retrospective nature, heterogeneity, and small sample size. ConclusionsSurgical management of tumors in HSKs can be approached via both open surgery and MIS, with maximal preservation of functional renal parenchyma. In this cohort, rates of complications, positive surgical margins, and renal functional decrease were acceptable, considering the anatomical complexity of these kidneys and tumors. These tumors display great variation in histological subtypes. Meticulous presurgical planning, taking advantage of advanced imaging techniques, can aid in achieving good outcomes. Patient summaryWe evaluated the surgical management of renal tumors in horseshoe kidneys, which are very rare. Although these procedures are highly complex, outcomes are acceptable. Modern imaging techniques are often required in presurgical planning.

CPAnet Registry-An International Chronic Pulmonary Aspergillosis Registry.

Chronic pulmonary aspergillosis (CPA) is a chronic fungal infection of the lung associated with high morbidity and mortality. The CPA Research network (CPAnet) registry established in 2018 is an international multicenter collaboration aiming to improve CPA knowledge and patient care. This study’s aim was to describe the data collection process and content of CPAnet registry with preliminary clinical data. In the CPAnet registry, clinical data are collected through a web-based questionnaire. Data include CPA phenotype, comorbidities, treatment, outcome, and follow-up from several international centers. An exemplary descriptive analysis was performed on 74 patients, who were registered online before April 2020. CPA patients were predominantly (72%) male, 39% had chronic obstructive pulmonary disease, and 68% had a history of smoking. Chronic cavitary pulmonary aspergillosis was the most common CPA subtype (62%). In 32 patients (52%), voriconazole was the preferred first-line therapy. The multicenter multinational CPAnet registry is a valuable approach to gather comprehensive data on a large study population and reflects real-world clinical practice rather than focusing on specific patient populations in more specialized centers. Additional CPA reference centers are being encouraged to join this promising clinical research collaboration.

The way forward to understand aortic disease.

Content List ‐ Read more articles from the symposium: “Uppsala Aortic summit”.

Management and outcomes of meningiomas secondary to childhood and adolescent radiation treatment

Abstract Background With the increased rate of childhood cancer survivors, a marked rise in the incidence of secondary intracranial meningiomas has been established. Objective Determine the outcomes of patients diagnosed with radiation-induced meningiomas (RIM). Methods Single-centre retrospective cohort study of patients with new or recurrent RIM (2007–2018). Results 47 patients were identified (21 females). Mean age at radiation was 15 years (SD=14) and the most common indications were leukaemia (n=8) and childhood brain tumours (n=35; medulloblastoma and pilocytic astrocytoma (n=7 each)). 93 de-novo meningiomas were identified. The median latency period between radiation and diagnosis was 28.5 years (IQR 22–37). 61% were asymptomatic whilst the remainder manifested headache (20%), focal neurological deficit (12%) and epilepsy (5%). 32 operated de-novo RIM revealed WHO grade I (n=19; 59%), WHO grade II (n=11; 34%) and 2 intraosseous meningiomas (n=2; 6%). After a median of 5 years (IQR 3–10), 9 (28%) operated RIM recurred/progressed. At recurrence, 5 were operated (3 WHO grade I, 2 WHO grade II and 1 WHO grade III), 2 patients were palliated and 2 remain under active observation. By the end of the study period, 20 patients were harbouring multiple meningiomas and 8 patients were deceased. Conclusion Radiation-induced meningioma should be monitored until symptomatic. Operated RIMs have a high recurrence rate. Further radiotherapy is not effective. Further clinical and genetic analyses as part of an international multi-centre collaboration are planned.

Comparative effectiveness of robotic assisted and open radical cystectomy in contemporary cohorts of bladder cancer patients: An international multicenter collaboration

Comparative effectiveness of robotic assisted and open radical cystectomy in contemporary cohorts of bladder cancer patients: An international multicenter collaboration

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration.

The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI)=0.87; 95% CI=0.799-0.93] marginally met the prespecified success criterion (lower 95% CI≥0.8), while the ICC for the hot-spot method (0.83; 95% CI=0.74-0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6min for global and hot-spot methods, respectively. The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.

Differences in trends in the use of robot-assisted and open radical cystectomy and changes over time in peri-operative outcomes among selected centres in North America and Europe: an international multicentre collaboration.

To compare trends in the use of robot-assisted radical cystectomy (RARC) and changes over time in peri-operative outcomes in selected North American and European centres. We conducted a retrospective evaluation of 2401 patients treated with open radical cystectomy (ORC) or RARC for bladder cancer at 12 centres in North America and Europe between 2006 and 2018. We used the Kruskal-Wallis and chi-squared test to evaluate differences between continuous and categorical variables. Overall, 49.5% of patients underwent RARC and 51.5% ORC. RARC became the most commonly performed procedure in contemporary patients, with an increase from 29% in 2006-2008 to 54% in 2015-2018 (P < 0.001). In the North American centres the use of RARC was higher than that of ORC from 2006, and remained stable over time, whereas in the European centres its use increased exponentially from 2% to 50%. In both groups patients who underwent RARC had less advanced T stages (P < 0.001), lower American Society of Anesthesiologists scores (P < 0.05), lower blood loss (P = 0.001) and shorter length of hospital stay (P < 0.05). No differences were found in early complications. Early readmission and re-operation rates were worse for patients treated with RARC in the European centres; however, when contemporary patients only were considered, the statistical significance was lost. The present study shows that the use of RARC has constantly increased since its introduction, overtaking ORC in the most contemporary series. While RARC was more frequently performed than ORC since its introduction in the North American centres and its use remained substantially stable over time, its use increased exponentially in the European centres. The different trends in use of RARC/ORC and changes over time in peri-operative outcomes between the North American and European centres can be attributed to the earlier introduction and spread of RARC in the former compared with the latter.

843 - Comparative effectiveness of robotic assisted and open radical cystectomy in contemporary cohorts of bladder cancer patients: An international multicenter collaboration

843 - Comparative effectiveness of robotic assisted and open radical cystectomy in contemporary cohorts of bladder cancer patients: An international multicenter collaboration

Abstract P4-02-01: Analytical validation of an automated digital scoring protocol for Ki67: International multicenter collaboration study

Abstract Background/Goal: Ki67 expression has been a valuable prognostic marker in breast cancer, but has not seen broad adoption due to lack of standardization between institutions. Automation could represent a solution. Here we tested 3 automated digital image analysis (DIA) platforms including an open source platform to: (i) Investigate the reproducibility of Ki67 measurement across platforms with supervised classifiers performed by the same operator and by multiple operators. (ii) Compare accuracy of the 3 DIA platforms against outcome (prognostic potential). (iii) Assess inter-laboratory reproducibility of a calibrated DIA tool to evaluate Ki67 in breast cancer among 10 participating labs of the International Ki67 in Breast Cancer Working Group (IKWG). Methods: The Mib-1 antibody (Dako) was used to detect Ki67 (dilution 1:100). HALO (H) (IndicaLabs), QuantCenter (QC) (3DHistech), QuPath (QP) (open-source software) digital image analysis (DIA) platforms were used to evaluate Ki67 expression. As a ground truth, we evaluated Ki67 LI with meticulous manual tissue segmentation using the Spectrum Webscope (SW) (Aperio). Calibration was performed using 30 ER+ breast cancer cases from phase 3 of the IKWG initiative where blocks were centrally cut and stained for Ki67. The inter-laboratory analysis was done with 10 participating laboratories divided into 2 groups where members within the same group were given the same set of images. The outcome cohort consisted of 149 breast cancer cases from the Yale Pathology archives in tissue microarray format. Intra-class correlation coefficient (ICC) was used to measure reproducibility with the pre-specified criterion for success being to exceed 0.80. Kaplan-Meier analysis supported with log-rank test was performed to assess prognostic potential. Results: All 3 DIA platforms showed excellent inter-platform reproducibility (ICC: 0.933, CI: 0.879-0.966). Also, excellent reproducibility was found between all DIA platforms and the reference standard Ki67 values of SW (QP ICC: 0.970, CI: 0.936-0.986; H ICC: 0.968, CI: 0.933-0.985; QC ICC: 0.964, CI: 0.919-0.983). The intra-DIA reproducibility was also excellent for all platforms (QP ICC: 0.992, CI: 0.986-0.996; H ICC: 0.972, CI: 0.924-0.988; QC ICC: 0.978, CI: 0.932-0.991). Comparing each DIA against outcome, the hazard ratios were similar (QP=3.309, H=3.077, QC=3.731). The inter-operator reproducibility was particularly high (ICC: 0.962-0.995). As QP is open source software and also showed the lowest intra-DIA platform variability, we selected the QP platform to investigate inter-laboratory reproducibility among 10 IKWG labs. The different-section ICC across the 10 labs was 0.974 (CI: 0.954 - 0.986). The same-section ICC estimate was 0.984 (CI: 0.971-0.992) for group 1 and 0.978 (CI: 0.956-0.989) for group 2. Conclusions: Our results showed outstanding reproducibility both within and between DIA platforms. We also found the platforms essentially indistinguishable with respect to prediction of breast cancer patient outcome. Automated Ki67 evaluation using a calibrated, open-source DIA platform (QuPath) met the pre-specified criterion of success in the multi-institutional setting. Assessment of clinical utility is planned. Citation Format: Acs B, Leung SC, Pelekanou V, Bai Y, Martinez-Morilla S, Toki M, Chang MC, Gholap A, Jadhav A, Hugh JC, Bigras G, Laurinavicius A, Augulis R, Levenson R, Todd A, Piper T, Virk S, van der Vegt B, Hayes DF, Dowsett M, Nielsen TO, Rimm DL. Analytical validation of an automated digital scoring protocol for Ki67: International multicenter collaboration study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-02-01.

Abstract P2-03-01: Analytical validation of a standardized scoring protocol for Ki67 assessed on breast excision whole sections: An international multicenter collaboration

Abstract Aims: (i) Determine whether between-observer reproducibility for Ki67 when assessed on whole sections according to a standardized scoring protocol is adequate for clinical application. (ii) Compare between-observer reproducibility of Ki67 scores assessed on hot-spots to scores using a global method that averages across a tissue section. Background: The nuclear proliferation biomarker Ki67 has multiple potential roles in breast cancer, including aiding decisions based on prognosis, but unacceptable levels of between-laboratory variability have been observed. The International Ki67 in Breast Cancer Working Group has undertaken a systematic program to determine whether Ki67 measurement can be analytically validated and standardized across labs. In phase 1, variability in visual interpretation was identified as an important source of variability. Phases 2 and 3a showed that adherence to defined scoring methods substantially improved reproducibility in scoring tissue microarrays and core-cut biopsies. We now assess whether acceptable reproducibility can be achieved on whole sections. Methods: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 to assemble 4 sets of 30 stained tumor sections, circulated around 23 labs in 12 countries. Ki67 was scored by 2 methods by all labs: (a) global: 4 fields of 100 tumor cells each were selected to reflect observed heterogeneity in nuclear staining (b) hot-spot: the field with highest Ki67 percentage of tumor cells with nuclear staining was selected and up to 500 cells scored. Ki67 scores were log2-transformed for statistical analyses and back-transformed for presentation. The primary objective was to assess whether either method could achieve an intraclass correlation coefficient (ICC) significantly greater than 0.8, considered substantial to almost-perfect reproducibility. Secondary objectives were to assess which method had highest observed ICC and to assess whether observers identified the same “hot-spots”. Results: ICC for the global method was 0.87 (95%CI: 0.799-0.93), marginally meeting the prespecified success criterion. The ICC for the hot-spot method was 0.83 (95%CI: 0.74-0.90) and had a CI extending below the success criterion. Across the 23 labs, geometric mean value of the 30 scores ranged from 8.5 to 19.6 for the global method and from 12.8 to 30.3 for the hot-spot method. The overall mean (95% CI) of these values was 12.9 (11.9-14.0) and 20.9 (19.1-22.8), respectively. Visually, between-laboratory agreement in location of selected hot-spot varies between cases. The median times for scoring were 9 and 6 minutes for global and hot-spot methods respectively. Conclusions: The global method marginally met the prespecified criterion of success; it should now be evaluated for clinical validity in appropriate cohorts of cases. The hot-spot method was observed to have slightly less reproducibility between labs. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between labs further. (Supported by a grant from the Breast Cancer Research Foundation) Citation Format: Nielsen TO, Leung SCY, Zabaglo LA, Arun I, Badve SS, Bane AL, Bartlet JMS, Borgquist S, Chang MC, Dodson A, Ehinger A, Fineberg S, Focke CM, Gao D, Gown AM, Gutierrez C, Hugh JC, Kos Z, Lænkholm A-V, Mastropasqua MG, Moriya T, Nofech-Mozes S, Osborne CK, Penault-Llorca FM, Piper T, Sakatani T, Salgado R, Starczynski J, Sugie T, van der Vegt B, Viale G, Hayes DF, McShane LM, Dowsett M. Analytical validation of a standardized scoring protocol for Ki67 assessed on breast excision whole sections: An international multicenter collaboration [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-03-01.

Guidelines for Assessment of Gait and Reference Values for Spatiotemporal Gait Parameters in Older Adults: The Biomathics and Canadian Gait Consortiums Initiative.

Background: Gait disorders, a highly prevalent condition in older adults, are associated with several adverse health consequences. Gait analysis allows qualitative and quantitative assessments of gait that improves the understanding of mechanisms of gait disorders and the choice of interventions. This manuscript aims (1) to give consensus guidance for clinical and spatiotemporal gait analysis based on the recorded footfalls in older adults aged 65 years and over, and (2) to provide reference values for spatiotemporal gait parameters based on the recorded footfalls in healthy older adults free of cognitive impairment and multi-morbidities.Methods: International experts working in a network of two different consortiums (i.e., Biomathics and Canadian Gait Consortium) participated in this initiative. First, they identified items of standardized information following the usual procedure of formulation of consensus findings. Second, they merged databases including spatiotemporal gait assessments with GAITRite® system and clinical information from the “Gait, cOgnitiOn & Decline” (GOOD) initiative and the Generation 100 (Gen 100) study. Only healthy—free of cognitive impairment and multi-morbidities (i.e., ≤ 3 therapeutics taken daily)—participants aged 65 and older were selected. Age, sex, body mass index, mean values, and coefficients of variation (CoV) of gait parameters were used for the analyses.Results: Standardized systematic assessment of three categories of items, which were demographics and clinical information, and gait characteristics (clinical and spatiotemporal gait analysis based on the recorded footfalls), were selected for the proposed guidelines. Two complementary sets of items were distinguished: a minimal data set and a full data set. In addition, a total of 954 participants (mean age 72.8 ± 4.8 years, 45.8% women) were recruited to establish the reference values. Performance of spatiotemporal gait parameters based on the recorded footfalls declined with increasing age (mean values and CoV) and demonstrated sex differences (mean values).Conclusions: Based on an international multicenter collaboration, we propose consensus guidelines for gait assessment and spatiotemporal gait analysis based on the recorded footfalls, and reference values for healthy older adults.

International Psychometric Validation of an EORTC Quality of Life Module Measuring Cancer Related Fatigue (EORTC QLQ-FA12).

The European Organisation for Research and Treatment of Cancer (EORTC) Group has developed a new multidimensional instrument measuring cancer-related fatigue to be used in conjunction with the quality of life core questionnaire (EORTC QLQ-C30). The module EORTC QLQ-FA13 assesses physical, cognitive, and emotional aspects of cancer-related fatigue. The methodology follows the EORTC guidelines for phase IV validation of modules. This paper focuses on the results of the psychometric validation of the factorial structure of the module. For validation and cross-validation confirmatory factor analysis (maximum likelihood estimation), intraclass correlation and Cronbach alpha for internal consistency were employed. The study involved an international multicenter collaboration of 11 European and non-European countries. A total of 946 patients with various tumor diagnoses were enrolled. Based on the confirmatory factor analysis, we could approve the three-dimensional structure of the module. Removing one item and reassigning the factorial mapping of another item resulted in the EORTC QLQ-FA12. For the revised scale, we found evidence supporting good local (indicator reliability ≥ 0.60, factor reliability ≥ 0.82) and global model fit (GFI t1|t2 = 0.965/0.957, CFI t1|t2 = 0.976/0.972, RMSEA t1|t2 = 0.060/0.069) for both measurement points. For each scale, test-retest reliability proved to be very good (intraclass correlation: R t1-t2 = 0.905-0.921) and internal consistency proved to be good to high (Cronbach alpha = .79-.90). Based on the former phase III module, the multidimensional structure was revised as a phase IV module (EORTC FA12) with an improved scale structure. For a comprehensive validation of the EORTC FA12, further aspects of convergent and divergent validity as well as sensitivity to change should be determined.

Radiotherapy for diffuse brainstem glioma in children and young adults.

Diffuse brainstem glioma is a devastating disease with very poor prognosis. The most commonly used radiological treatment is conventional fractionated radiation. So far, there is no meta-analysis or systematic review available that assesses the benefits or harms of radiation in people with diffuse brainstem glioma. To assess the effects of conventional fractionated radiotherapy (with or without chemotherapy) versus other therapies (including different radiotherapy techniques) for newly diagnosed diffuse brainstem gliomas in children and young adults aged 0 to 21 years. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed, and EMBASE to 19 August 2015. We scanned conference proceedings from the International Society for Paediatric Oncology (SIOP), International Symposium on Paediatric Neuro-Oncology (ISPNO), Society of Neuro-Oncology (SNO), and European Association of Neuro-Oncology (EANO) from 1 January 2010 to 19 August 2015. We searched trial registers including the International Standard Randomised Controlled Trial Number (ISRCTN) Register, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the register of the National Institutes of Health to 19 August 2015. We imposed no language restrictions. All randomised controlled trials (RCTs), quasi-randomised trials (QRCTs), or controlled clinical trials (CCTs) that compared conventional fractionated radiotherapy (with or without chemotherapy) versus other therapies (including different radiotherapy techniques) for newly diagnosed diffuse brainstem glioma in children and young adults aged 0 to 21 years. Two review authors independently screened studies for inclusion, extracted data, assessed the risk of bias in each eligible trial, and conducted GRADE assessment of included studies. We resolved disagreements through discussion. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We identified two RCTs that fulfilled our inclusion criteria. The two trials tested different comparisons.One multi-institutional RCT included 130 participants and compared hyperfractionated radiotherapy (six-week course with twice a day treatment of 117 cGy per fraction to a total dose of 7020 cGy) with conventional radiotherapy (six-week course with once a day treatment of 180 cGy per fraction to a total dose of 5400 cGy). The median time overall survival (OS) was 8.5 months in the conventional group and 8.0 months in the hyperfractionated group. We detected no clear evidence of effect on OS or event-free survival (EFS) in participants receiving hyperfractionated radiotherapy compared with conventional radiotherapy (OS: hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.75 to 1.53; EFS: HR 1.26, 95% CI 0.83 to 1.90). Radiological response (risk ratio (RR) 0.94, 95% CI 0.54 to 1.63) and various types of toxicities were similar in the two groups. There was no information on other outcomes. According to the GRADE approach, we judged the quality of evidence to be low (i.e. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate) for OS and EFS, and very low (i.e. we are very uncertain about the estimate) for radiological response and toxicities.The second RCT included 71 participants and compared hypofractionated radiotherapy (39 Gy in 13 fractions over 2.6 weeks, 3 Gy per fraction) with conventional radiotherapy (54 Gy in 30 fractions over six weeks, 1.8 Gy per fraction). This trial reported a median OS of 7.8 months for the hypofractionated group and 9.5 months for the conventional group. It reported a progression-free survival (PFS) of 6.3 months for the hypofractionated group and 7.3 months for the conventional group. We found no clear evidence of effect on OS (HR 1.03, 95% CI 0.53 to 2.01) or PFS (HR 1.19, 95% CI 0.63 to 2.22) in participants receiving hypofractionated radiotherapy when compared with participants receiving conventional radiotherapy. The mainly observed adverse effect was local erythema and dry desquamation especially behind the auricles. There were some other toxicities, but there was no statistically significant difference between treatment groups. There was no information on other outcomes. We judged the quality of evidence to be moderate (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) for OS, and low for PFS and toxicities. It should be mentioned that the sample size in this RCT was small, which could lead to insufficient statistical power for a clinically relevant outcome. We could make no definitive conclusions from this review based on the currently available evidence. Further research is needed to establish the role of radiotherapy in the management of newly diagnosed diffuse brainstem glioma in children and young adults. Future RCTs should be conducted with adequate power and all relevant outcomes should be taken into consideration. Moreover, international multicentre collaboration is encouraged. Considering the potential advantage of hypofractionated radiotherapy to decrease the treatment burden and increase the quality of remaining life, we suggest that more attention should be paid to hypofractionated radiotherapy.

Clinical characteristics and outcomes of patients with Hodgkin lymphoma with central nervous system involvement: An international multicenter collaboration.

Central nervous system (CNS) involvement is rare in patients with Hodgkin lymphoma (HL). Thus, the clinical features and outcomes are not well described. Cases of histologically confirmed CNS HL diagnosed between 1995 and 2015 were retrospectively identified in institutional (n = 7), national (n = 2), and cooperative group (n = 1) databases. We screened 30,781 patients with HL in our combined databases and identified 21 patients meeting eligibility criteria, an estimated frequency of 0.07%. CNS involvement was present at initial diagnosis in 10 patients (48%) and a feature of relapsed/refractory disease in 11 (52%). Among these 11 patients, the median time from initial diagnosis of HL to development of CNS involvement was 1.9 years (range 0.4-6.6) and the median number of prior lines of therapy was 2 (range 1-7). Altogether, treatments included radiation, multiagent systemic chemotherapy, combined modality therapy, and subtotal resection. The overall response rate was 65%. After a median follow-up of 3.6 years (range 0.8-13.2) from diagnosis of CNS HL, the median PFS and OS were 7.6 and 29 months, respectively. CNS involvement as a feature of relapsed/refractory disease was adversely prognostic for both PFS and OS; however, four patients remain alive and free of relapse at 7-78 months follow-up. CNS involvement in HL is exceedingly rare and has a distinct clinical presentation with predilection for parenchymal lesions with dural extension. Around one-quarter of patients, mostly with CNS involvement at initial HL diagnosis, experience prolonged disease-free survival. Am. J. Hematol. 91:894-899, 2016. © 2016 Wiley Periodicals, Inc.

Analytical validation of a standardized scoring protocol for Ki67: phase 3 of an international multicenter collaboration.

Pathological analysis of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers. However, clinical utility of the immunohistochemical (IHC) assay for Ki67 immunohistochemistry has been hampered by unacceptable between-laboratory analytical variability. The International Ki67 Working Group has conducted a series of studies aiming to decrease this variability and improve the evaluation of Ki67. This study tries to assess whether acceptable performance can be achieved on prestained core-cut biopsies using a standardized scoring method. Sections from 30 primary ER+ breast cancer core biopsies were centrally stained for Ki67 and circulated among 22 laboratories in 11 countries. Each laboratory scored Ki67 using three methods: (1) global (4 fields of 100 cells each); (2) weighted global (same as global but weighted by estimated percentages of total area); and (3) hot-spot (single field of 500 cells). The intraclass correlation coefficient (ICC), a measure of interlaboratory agreement, for the unweighted global method (0.87; 95% credible interval (CI): 0.81–0.93) met the prespecified success criterion for scoring reproducibility, whereas that for the weighted global (0.87; 95% CI: 0.7999–0.93) and hot-spot methods (0.84; 95% CI: 0.77–0.92) marginally failed to do so. The unweighted global assessment of Ki67 IHC analysis on core biopsies met the prespecified criterion of success for scoring reproducibility. A few cases still showed large scoring discrepancies. Establishment of external quality assessment schemes is likely to improve the agreement between laboratories further. Additional evaluations are needed to assess staining variability and clinical validity in appropriate cohorts of samples.