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Topic To determine the age up to which children are at risk of trilateral retinoblastoma (TRb) developing, whether its onset is linked to the age at which intraocular retinoblastomas develop, and the lead time from a detectable pineal TRb to symptoms. Clinical relevance Approximately 45% of patients with retinoblastoma—those with a germline RB1 pathogenic variant—are at risk of pineal TRb developing. Early detection and treatment are essential for survival. Current evidence is unclear regarding the usefulness of screening for pineal TRb and, if useful, the age up to which screening should be continued. Methods We conducted a study according to the Meta-analysis of Observational Studies in Epidemiology guidelines for reporting meta-analyses of observational studies. We searched PubMed and Embase between January 1, 1966, and February 27, 2019, for published literature. We considered articles reporting patients with TRb with survival and follow-up data. Inclusion of articles was performed separately and independently by 2 authors, and 2 authors also independently extracted the relevant data. They resolved discrepancies by consensus. Results One hundred thirty-eight patients with pineal TRb were included. Of 22 asymptomatic patients, 21 (95%) were diagnosed before the age of 40 months (median, 16 months; interquartile range, 9–29 months). Age at diagnosis of pineal TRb in patients diagnosed with retinoblastoma at 6 months or younger versus older than 6 months were comparable (P = 0.44), suggesting independence between the ages at diagnosis of intraocular retinoblastoma and pineal TRb. The laterality of intraocular retinoblastoma and its treatment were not associated with the age at which pineal TRb was diagnosed. The lead time from asymptomatic to symptomatic pineal TRb was approximately 1 year. By performing a screening magnetic resonance imaging scan every 6 months after the diagnosis of heritable retinoblastoma (median age, 6 months) until 36 months of age, at least 311 and 776 scans would be required to detect 1 case of asymptomatic pineal TRb and to save a single life, respectively. Conclusions Patients with retinoblastoma are at risk of pineal TRb developing for a shorter period than previously assumed, and the age at diagnosis of pineal TRb is independent of the age at diagnosis of retinoblastoma. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) level of evidence for these conclusions remains low.

Background and purpose: In head and neck squamous cell carcinoma (HNSCC) (chemo)radiotherapy is increasingly used to preserve organ functionality. The purpose of this study was to identify predictive pretreatment DWI- and 18F-FDG-PET/CT-parameters for treatment failure (TF), locoregional recurrence (LR) and death in HNSCC patients treated by (chemo)radiotherapy. Materials and methods: We retrospectively included 134 histologically proven HNSCC patients treated with (chemo)radiotherapy between 2012-2017. In 58 patients pre-treatment DWI and 18F-FDG-PET/CT were performed, in 31 patients DWI only and in 45 patients 18F-FDG-PET/CT only. Primary tumor (PT) and largest lymph node (LN) metastasis were quantitatively assessed for TF, LR and death. Multivariate analysis was performed for 18F-FDG-PET/CT and DWI separately and thereafter combined. In patients with both imaging modalities, positive and negative predictive value in TF and differences in LR and death, were assessed. Results: Mean follow-up was 25.6 months (interquartile-range; 14.0–37.1 months). Predictors of treatment failure, corrected for TNM-stage and HPV-status, were SUVmax-PT, ADCmax-PT, total lesion glycolysis (TLG-LN), ADCp20-LN (P = 0.049, P = 0.024, P = 0.031, P = 0.047, respectively). TLG-PT was predictive for LR (P = 0.003). Metabolic active tumor volume (MATV-PT) (P = 0.003), ADCGTV-PT (P < 0.001), ADCSD (P = 0.048) were significant predictors for death. In patients with both imaging modalities SUVmax-PT remained predictive for treatment failure (P = 0.049), TLG-LN for LR (P = 0.003) and ADCGTV-PT for death (P < 0.001). Higher predictive value for treatment failure was found for the combination of SUVmax-PT and ADCmax-PT, compared to either one separately. Conclusion: Both DWI- and 18F-FDG-PET/CT-parameters appear to have predictive value for treatment failure, locoregional recurrence and death. Combining SUVmax-PT and ADCmax-PT resulted in better prediction of treatment failure compared to single parameter assessment.

ObjectivesTo assess disease-free survival (DFS) in head and neck squamous cell carcinoma (HNSCC) treated with (chemo)radiotherapy ([C]RT).MethodsPretreatment MR-images of 78 patients were retrospectively studied. Apparent diffusion coefficients (ADC) were calculated with two sets of two b-values: 0–750s/mm2 (ADC750) and 0–1000s/mm2 (ADC1000). One observer assessed tumor volume on T1-WI. Two independent observers assessed ADC-values of primary tumor and largest lymph node in two sessions (i.e. without and with including CE-T1WI in image analysis). Interobserver and intersession agreement were assessed with intraclass correlation coefficients (ICC) separately for ADC750 and ADC1000. Lesion volumes and ADC-values were related to DFS using Cox regression analysis.ResultsMedian follow-up was 18 months. Interobserver ICC was better without than with CE-T1WI (primary tumor: 0.92 and 0.75–0.83, respectively; lymph node: 0.81–0.83 and 0.61–0.64, respectively). Intersession ICC ranged from 0.84 to 0.89. With CE-T1WI, mean ADC-values of primary tumor and lymph node were higher at both b-values than without CE-T1WI (P

Purpose To determine and compare the diagnostic performance of magnetic resonance imaging (MRI) and computed tomography (CT) for the diagnosis of tumor extent in advanced retinoblastoma, using histopathologic analysis as the reference standard. Design Systematic review and meta-analysis. Participants Patients with advanced retinoblastoma who underwent MRI, CT, or both for the detection of tumor extent from published diagnostic accuracy studies. Methods Medline and Embase were searched for literature published through April 2013 assessing the diagnostic performance of MRI, CT, or both in detecting intraorbital and extraorbital tumor extension of retinoblastoma. Diagnostic accuracy data were extracted from included studies. Summary estimates were based on a random effects model. Intrastudy and interstudy heterogeneity were analyzed. Main Outcome Measures Sensitivity and specificity of MRI and CT in detecting tumor extent. Results Data of the following tumor-extent parameters were extracted: anterior eye segment involvement and ciliary body, optic nerve, choroidal, and (extra)scleral invasion. Articles on MRI reported results of 591 eyes from 14 studies, and articles on CT yielded 257 eyes from 4 studies. The summary estimates with their 95% confidence intervals (CIs) of the diagnostic accuracy of conventional MRI at detecting postlaminar optic nerve, choroidal, and scleral invasion showed sensitivities of 59% (95% CI, 37%–78%), 74% (95% CI, 52%–88%), and 88% (95% CI, 20%–100%), respectively, and specificities of 94% (95% CI, 84%–98%), 72% (95% CI, 31%–94%), and 99% (95% CI, 86%–100%), respectively. Magnetic resonance imaging with a high (versus a low) image quality showed higher diagnostic accuracies for detection of prelaminar optic nerve and choroidal invasion, but these differences were not statistically significant. Studies reporting the diagnostic accuracy of CT did not provide enough data to perform any meta-analyses. Conclusions Magnetic resonance imaging is an important diagnostic tool for the detection of local tumor extent in advanced retinoblastoma, although its diagnostic accuracy shows room for improvement, especially with regard to sensitivity. With only a few—mostly old—studies, there is very little evidence on the diagnostic accuracy of CT, and generally these studies show low diagnostic accuracy. Future studies assessing the role of MRI in clinical decision making in terms of prognostic value for advanced retinoblastoma are needed.

Background and purpose Timely detection of recurrent laryngeal tumor after radiation is an important predictive factor for curation as well as preservation of laryngeal function. Direct laryngoscopy under general anesthesia with taking of biopsies is the standard diagnostic procedure to detect recurrence when suspicion is raised. This, however, is an invasive and potentially damaging technique. Hence, a non-invasive diagnostic procedure, such as 18 FDG-PET to stratify patients for direct laryngoscopy could be useful. 18 FDG-PET is interpreted visually so that observer variation may affect clinical practice. In the present study, we therefore investigated this aspect of reproducibility. Patients and methods Thirty consecutive patients suspected of recurrent laryngeal carcinoma after radiotherapy underwent 18 FDG-PET and direct laryngoscopy under general anesthesia with taking of biopsies. 18 FDG-PET scans were reported by nine nuclear medicine physicians and residents, using a three-point scaling system. The reference was the absence or appearance of a local recurrence in the 12 months following 18 FDG-PET. Results Eight patients had biopsy proven recurrent laryngeal carcinoma. Sensitivity of 18 FDG-PET was 88% (95% CI 53–98%) and specificity was 82% (95% CI 62–93%). The observers had a moderate to reasonable agreement (weighted kappa 0.45 (95% CI 0.20–0.69)) vs. the clinical gold standard and interobserver kappa was 0.54 (95% CI 0.40–0.69). Conclusion 18 FDG-PET seems to be a promising technique to detect recurrent laryngeal carcinoma after radiotherapy, and selecting patients for direct laryngoscopy. This will avoid futile invasive procedures. Interobserver agreement and variability is reasonable using this technique, but training is necessary. Studies comparing different strategies to select patients for direct laryngoscopy in case of suspected recurrence are warranted.

Cervical lymph nodes (CLN) have been described to be the first lymphoid draining site of the brain. In this study we used ultrasound guided fine needle aspiration cytology (USgFNAC) to obtain cells, in vivo, from non-enlarged CLN of multiple sclerosis (MS) patients and HCs (HC), and investigated whether myelin proteins could be detected. Macrophages containing myelin basic protein (MBP) and proteolipid protein (PLP) were found in CLN of all MS patients, whereas these could only be detected in a minority of HC. This novel approach allows investigation of the first draining site of the brain for in vivo analysis of the immune regulation of MS.

Since the diagnosis of multiple sclerosis (MS) may not be clear on clinical grounds or from other paraclinical tests, and due to the necessary assessment of new pharmacological therapeutical agents which demand objective outcome parameters for relatively short trials, magnetic resonance imaging (MRI) is not only used to diagnose MS, but is also broadly used to monitor disease progression. In exploratory trials, where MRI is used as a primary outcome measure, serial scans are used to detect disease activity as the number of active lesions showing signal enhancement after gadolinium administration. When the results is positive, the drug has to be tested further in a phase III study, using clinical endpoints as primary outcome measurements. MRI can be used as a secondary outcome measure. Given the uncertain relation between MRI and clinical findings, MR findings provide only supportive evidence. Serial scans (usually yearly) are used to monitor disease progression as an increase in total lesion load. Consequently, reproducibility of the lesions and therefore spatial resolution, should be maximized. Several putative treatments have been assessed using MR monitoring in phase II and phase III trials. A multitude of phase II trials have shown that it is indeed possible to demonstrate that MR is capable of showing, even in small groups, whether new drugs have any effect on the development of lesions.

Imaging of the neck for the assessment of nodal metastases can be used to detect occult metastases or to assess operability of palpable metastases. The detection of small occult metastases has limitations, as micrometastases cannot be depicted. However, imaging can diminish the risk of occult metastases and thus influence management; for this purpose a very sensitive technique is necessary. The currently used radiologic criteria are not sensitive enough to accomplish enough reduction in the risk of occult metastases. Therefore, more sensitive CT and MRI criteria, but especially ultrasound guided aspiration, should be used to assess the clinically negative neck.

Lymphatic metastasis is the most important mechanism in the spread of head and neck squamous cell carcinomas. The rate of metastasis probably reflects the aggressiveness of the primary tumor and is an important prognosticator. 55,59,94,128 Not only the presence, but also the number of nodal metastases, the level in the neck, the size of the nodes, and the presence of extranodal spread are important prognostic features. In most institutions throughout the world, the neck is mainly staged by palpation. Although palpation has the advantage of being both easy and inexpensive to perform and repeat, it is generally accepted to be inaccurate. Both the sensitivity and specificity are in the range of 60% to 70%, depending on the tumor site studied. 4,90 As a consequence of the low sensitivity of palpation, a neck side without palpable metastases is at risk of harboring occult metastasis. This risk is to a large extent dependent on the size and site and other characteristics of the primary tumor. 34,56,60,71 For example, in glottic carcinomas and in small sinonasal carcinomas the risk of occult metastases is far below 10%. On the other hand, nasopharyngeal carcinomas, and to a lesser extent other pharyngeal carcinomas, have a risk of occult metastases of 50% or more. For most T1 to T3 oral, oropharyngeal, and supraglottic tumors this risk of occult metastases is in the range of 20% to 50%, with significant differences between different sites and studies. 46,58,64,74,87,93,96 In many head and neck primaries not only the ipsilateral site of the neck is at risk but the contralateral site has a significant risk to harbor metastases as well, especially when the primary has grown close to or extends over the midline. Because of the fallibility of palpation, it is widely accepted to treat the neck electively if the risk of occult metastases is high. The "acceptable" risk to perform elective treatment is very hard to define. As most clinicians do not treat the neck electively in small T1 oral carcinomas that carry a risk of around 15% of occult metastases, this figure is often quoted. Recently a meta-analysis using a decision analysis model on the basis of prognostic literature data was performed. In this study, a risk of occult metastases higher than 20% was calculated to be optimal for elective treatment. 134

Purpose To estimate the incidence of trilateral retinoblastoma in patients with retinoblastoma. Design Systematic review and meta-analysis. Methods We searched Medline and Embase for scientific literature published between January 1966 and July 2015 that assessed trilateral retinoblastoma incidence. We used a random-effects model for the statistical analyses. Results We included 23 retinoblastoma cohorts from 26 studies. For patients with bilateral retinoblastoma the unadjusted chance of developing trilateral retinoblastoma across all cohorts was 5.3% (95% confidence interval [CI]: 3.3%–7.7%); the chance of pineal trilateral retinoblastoma was 4.2% (95% CI: 2.6%–6.2%) and the chance of nonpineal trilateral retinoblastoma was 0.8% (95% CI: 0.4%–1.3%). In patients with hereditary retinoblastoma (all bilateral cases, and the unilateral cases with a family history or germline RB1 mutation) we found a trilateral retinoblastoma incidence of 4.1% (95% CI: 1.9%–7.1%) and a pineal trilateral retinoblastoma incidence of 3.7% (95% CI: 1.8%–6.2%). To reduce the risk of overestimation bias we restricted analysis to retinoblastoma cohorts with a minimum size of 100 patients, resulting in adjusted incidences of 3.8% (95% CI: 2.4%–5.4%), 2.9% (95% CI: 1.9%–4.2%), and 0.7% (95% CI: 0.3%–1.2%) for any, pineal, and nonpineal trilateral retinoblastoma, respectively, among patients with bilateral retinoblastoma. Among hereditary retinoblastoma we found an adjusted trilateral retinoblastoma incidence of 3.5% (95% CI: 1.2%–6.7%) and a pineal trilateral retinoblastoma incidence of 3.2% (95% CI: 1.4%–5.6%). Conclusion The estimated incidence of trilateral retinoblastoma is lower than what is reported in previous literature, especially after exclusion of small cohorts that were subject to overestimation bias in this context.