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Renal masses are commonly encountered on cross-sectional imaging examinations performed for nonrenal indications. Although most can be dismissed as benign cysts, a subset will be either indeterminate or suspicious; in many cases, imaging cannot be used to reliably differentiate between benign and malignant masses. On-going research in defining characteristics of common renal masses on advanced imaging shows promise in offering solutions to this issue. A recent update of the Bosniak classification (used to categorize cystic renal masses) was proposed with the goals of decreasing imaging follow-up in likely benign cystic masses, and therefore avoiding unnecessary surgical resection of such masses.

BackgroundThis study aimed to identify and resolve discordant variant interpretations across clinical molecular genetic laboratories through the Canadian Open Genetics Repository (COGR), an online collaborative effort for variant sharing and interpretation.MethodsLaboratories uploaded variant data to the Franklin Genoox platform. Reports were issued to each laboratory, summarising variants where conflicting classifications with another laboratory were noted. Laboratories could then reassess variants to resolve discordances. Discordance was calculated using a five-tier model (pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), benign (B)), a three-tier model (LP/P are positive, VUS are inconclusive, LB/B are negative) and a two-tier model (LP/P are clinically actionable, VUS/LB/B are not). We compared the COGR classifications to automated classifications generated by Franklin.ResultsTwelve laboratories submitted classifications for 44 510 unique variants. 2419 variants (5.4%) were classified by two or more laboratories. From baseline to after reassessment, the number of discordant variants decreased from 833 (34.4% of variants reported by two or more laboratories) to 723 (29.9%) based on the five-tier model, 403 (16.7%) to 279 (11.5%) based on the three-tier model and 77 (3.2%) to 37 (1.5%) based on the two-tier model. Compared with the COGR classification, the automated Franklin classifications had 94.5% sensitivity and 96.6% specificity for identifying actionable (P or LP) variants.ConclusionsThe COGR provides a standardised mechanism for laboratories to identify discordant variant interpretations and reduce discordance in genetic test result delivery. Such quality assurance programmes are important as genetic testing is implemented more widely in clinical care.

To report BRCA1 and BRCA2 (BRCA1/2) variant reassessments and reclassifications between 2012 and 2017 at the Advanced Molecular Diagnostics Laboratory (AMDL) in Toronto, Canada, which provides BRCA1/2 testing for patients in Ontario, and to compare AMDL variant classifications with submissions in ClinVar. Variants were assessed using a standardized variant assessment tool based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology’s guidelines and tracked in an in-house database. Variants were shared through the Canadian Open Genetics Repository and submitted to ClinVar for comparison against other laboratories. AMDL identified 1209 BRCA1/2 variants between 2012 and 2017. During this period, 32.9% (398/1209) of variants were reassessed and 12.4% (150/1209) were reclassified. The majority of reclassified variants were downgraded (112/150, 74.7%). Of the reclassified variants, 63.3% (95/150) were reclassified to benign, 20.7% (31/150) to likely benign, 10.0% (15/150) to variant of uncertain significance, 2.0% (3/150) to likely pathogenic, and 4.0% (6/150) to pathogenic. Discordant ClinVar submissions were found for 40.4% (488/1209) of variants. BRCA1/2 variants may be reclassified over time. Reclassification presents ethical and practical challenges related to recontacting patients. Data sharing is essential to improve variant interpretation, to help patients receive appropriate care based on their genetic results.

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. Methods: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record–derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. Results: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier; NCT03394859.

PurposeThe ClinGen Variant Curation Expert Panels (VCEPS) provide disease-specific rules for accurate variant interpretation. Using hearing loss-specific American College of Medical Genetics/Association for Molecular Pathology (HL-specific ACMG/AMP) guidelines, the ClinGen Hearing Loss VCEP (HL VCEP) illustrates the utility of expert specifications in resolving conflicting variant interpretations.MethodsA total of 157 variants across nine hearing loss genes were curated and submitted to ClinVar by the HL VCEP. The curation process consisted of collecting published and unpublished data for each variant by biocurators, followed by bi-monthly meetings of an expert curation subgroup that reviewed all evidence and applied the HL-specific ACMG/AMP guidelines to reach a final classification.ResultsBefore expert curation, 75% (117/157) of variants had single or multiple VUS submissions (17/157) or had conflicting interpretations in ClinVar (100/157). After applying the HL-specific ACMG/AMP guidelines, 24% (4/17) of VUS variants and 69% (69/100) of discordant variants were resolved into Benign (B), Likely Benign (LB), Likely Pathogenic (LP), or Pathogenic (P). Overall, 70% (109/157) variants had unambiguous classifications (B, LB, LP, P). We quantify the contribution of the HL-specified ACMG/AMP codes to variant interpretation.ConclusionExpert specification and application of the HL-specific ACMG/AMP guidelines effectively resolved discordant interpretations in ClinVar. This study supports the utility of ClinGen VCEPs in helping the community move towards more consistent variant interpretations, which will improve the care of patients with genetic disorders.

A 2-month-old male harboring a duplication of DMD exons 1-7 classified as pathogenic by an outside institution presented with mildly elevated CK levels; molecular breakpoint analysis by our laboratory reclassified the duplication as likely benign. To date, proband continues to develop normally with decreased CK levels, further supporting our reclassification.

Objective We investigated the proportions of and reclassified BRCA1/2 variants of unknown significance (VUS) in Korean patients with epithelial ovarian, tubal, and primary peritoneal cancers. Methods Data from 805 patients who underwent genetic testing for BRCA1/2 from January 1, 2006 to August 31, 2018 were included. The VUS in BRCA1/2 were reclassified using the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines. Results A BRCA1 pathogenic variant was found in 17.0% (137/805) of the patients, and BRCA1 VUS were found in 15.9% (128/805) of the patients. Further, 8.7% (69/805) of the patients possessed a BRCA2 pathogenic variant and 18.4% (148/805) of the patients possessed BRCA2 VUS. Fifty-three specific BRCA1 VUS were found and 20 were further reclassified as benign (n=11), likely benign (n=5), likely pathogenic (n=3), and pathogenic (n=1). The remaining 33 remained classified as VUS. For BRCA2, 55 specific VUS were detected; among these, 14 were reclassified as benign or likely benign, and 2 were reclassified as likely pathogenic. Among the 805 patients, 195 were found to have only VUS and no pathogenic variants (PV), and 41.5% (81/195) were reclassified as benign or likely benign, and 10.3% (20/195) as pathogenic or likely pathogenic variants. Conclusions Approximately 33.3% (36/108) of the specific BRCA1/2 variants analyzed in this study that were initially classified as VUS over a 13-year period were reclassified. Among these, 5.6% (6/108) were reclassified as pathogenic or likely pathogenic variants.

PurposeEfforts have been made by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology to make variant classification more uniform, but many limitations remain. Reclassification of a variant of uncertain significance (VUS) is expected, but other more certain calls, like pathogenic or benign, can also be reclassified once additional information is gathered. Variant reclassification can create difficult circumstances for both patients and clinicians.MethodsRetrospective review of all variant reclassifications in genes associated with hereditary cancer syndromes at one clinic between September 2013 and February 2017 was completed. All variant reclassifications were completed and reported by the original testing laboratory.ResultsA total of 1,103 hereditary cancer tests were ordered. Fewer than 5% (40/1,103) of the initial reports were updated during that time period. Most reclassifications (29/40) were downgrades of VUS to likely benign. Only three reclassifications could potentially alter medical management.ConclusionThe majority of variant reclassifications do not impact medical management. Upgrading a variant call to pathogenic could be important for a patient's care and shows the importance of open communication between laboratories and clinicians. A variant downgrade from pathogenic can be a significant reclassification as well, especially if prophylactic surgery has been completed.

Objective To investigate the utility of a detailed medical history in the interpretation of chromosomal microarray results for pediatric patients with a constitutional disease. Study design A retrospective review and reinterpretation of test results from chromosomal microarrays performed from 2011 to 2013. Previously reported genetic variants were reanalyzed after review of the patient's complete electronic medical record (cEMR). A 3-tier system was used for reclassification of variants: pathogenic or likely pathogenic (P/LP); variant of uncertain significance (VUS); or benign or likely benign (B/LB). Results Over an 18-month period, 998 patients with chromosomal microarray results were identified. The most common reasons for chromosomal microarray testing were developmental delay (n = 336), autism spectrum disorder (n = 241), and seizures (n = 143). Chromosomal microarray testing identified 1 or more variants in 48% (482 of 998) of patients; 516 patients had a negative report. For the 482 patients with variants, the original interpretations were composed of 19.3% P/LP (93 of 482), 44.8% VUS (216 of 482), and 35.9% B/LB (173 of 482) variants. After review of the cEMR, 34% of patient results (164 of 482) were changed in interpretation. One case changed from B/LB to VUS, 7 VUS were upgraded to P/LP, and 156 VUS were downgraded to B/LB. No P/LP variants had a change in interpretation. Conclusions Overall, 16.4% (164 of 998) of patients with chromosomal microarray testing had a change in interpretation. Access to the patient's cEMR improves the interpretation of chromosomal microarrays by decreasing the number of uncertain (VUS) interpretations.

The clinical utility of BRCA1/2 genotyping was recently extended from the selection of subjects at high risk for hereditary breast and ovary cancer to the identification of candidates for poly (ADP-ribose) polymerase (PARP) inhibitor treatment. This underscores the importance of accurate interpretation of BRCA1/2 genetic variants and of reducing the number of variants of uncertain significance (VUSs). Two recent studies by Findlay et al. and Starita et al. introduced high-throughput functional assays, and proactively analyzed variants in specific regions regardless of whether they had been previously observed. We retrospectively reviewed all BRCA1 and BRCA2 germline genetic test reports from patients with breast or ovarian cancer examined at Asan Medical Center (Seoul, Korea) between September 2011 and December 2018. Variants were assigned pathogenic or benign strong evidence codes according to the functional classification and were reclassified according to the ACMG/AMP 2015 guidelines. Among 3684 patients with available BRCA1 and BRCA2 germline genetic test reports, 429 unique variants (181 from BRCA1) were identified. Of 34 BRCA1 variants intersecting with the data reported by Findlay et al., three missense single-nucleotide variants from four patients (0.11%, 4/3684) were reclassified from VUSs to likely pathogenic variants. Four variants scored as functional were reclassified into benign or likely benign variants. Three variants that overlapped with the data reported by Starita et al. could not be reclassified. In conclusion, proactive high-throughput functional study data are useful for the reclassification of clinically observed VUSs. Integrating additional evidence, including functional assay results, may help reduce the number of VUSs.

Purpose To evaluate for stability of perifissural nodules (PFNs) in a dedicated oncologic population. Methods A retrospective review of 500 computed tomography (CT) chests from oncologic patients at our tertiary care cancer center with at least a three year follow up yielded 76 patients with PFNs. Patients with metastases on baseline CT chest were excluded (n = 14) as the presence of a PFN would not be clinically relevant, thus our final patient cohort was 62 patients with a total of 112 PFNs. PFN features, clinical features, and ancillary information was recorded from the CT and the electronic medical record for all patients. The two patient cohorts—stable or decreased PFN vs. increased PFN—were then compared. Results 112 PFNs were examined in 62 patients with a median follow up interval of 5.7 years. Of 62 patients, 59 (95.2%, 95% CI: 86.5, 99.0) had decreased/stable PFNs on follow up scan (median follow up 5.6 years) and 3 (4.8%, 95% CI: 1.0, 13.5%) had enlarged PFNs (median follow up 6.3 years). None of the PFN features, clinical features, nor ancillary information from the CT proved to be statistically significant. Conclusions Despite the lack of statistically significant distinguishing features to predict growth, our results are reassuring, since the majority of PFNs in our oncology patients were decreased or unchanged in size which is comparable to previously published data on PFNs in non-oncologic patients. Thus, we can similarly presume these nodules are most likely benign and can provide reassurance to our oncologic colleagues and our patients. Larger studies are warranted to further evaluate PFNs in the oncologic population which also examines the nodules by cancer type.

BACKGROUND In pregnant women with advanced maternal age (AMA) and fetuses with ultrasonographic (USG) soft markers it is always challenging to decide whether to implement chromosomal microarray analysis (CMA) or not. It is unclear whether CMA should be used in the fetuses with isolated USG soft markers, and there is still a lack of extensive sample research. MATERIAL AND METHODS We enrolled 1521 cases in our research and divided them into 3 groups as follows: pregnant women with isolated AMA (group 1, n=633), pregnant women whose fetuses had isolated USG soft markers (group 2, n=750), and pregnant women with AMA whose fetuses had isolated USG soft markers (group 3, n=138). All pregnant women underwent prenatal ultrasound and amniocentesis, and fetal cells in the amniotic fluid were used for genetic analysis of CMA. All participants signed a written informed consent prior to CMA. RESULTS Abnormal findings were detected by CMA in 330 (21.70%) fetuses, including 37 (2.43%) clinically significant copy number variations (CNVs), 52 (3.42%) benign or likely benign CNVs, and 240 (15.78%) variants of unknown significance. The frequency of clinically significant CNVs in group 1 and group 2 were significantly lower than that in group 3 (2.37% and 2.0% vs 5.07%, P

Trisomy 9p is one of the most common chromosomal partial trisomies in newborns. However, reports on prenatal 9p microduplications are rare in the clinic. This study aimed to examine the genotype–phenotype correlation and assess the clinical significance of 9p24.3 microduplication encompassing the DOCK8 gene. Eight pregnant women underwent amniocentesis for cytogenetic and genetic testing for various indications for prenatal diagnosis from January 2019 to January 2020. Chromosomal karyotypic analysis was performed on G-band metaphases that were prepared from cultured amniotic fluid cells. Chromosomal microarray analysis was carried out to detect chromosomal copy number variations. We also performed a literature review on clinical data on similar 9p24.3 microduplications to determine the genotype–phenotype correlation. We detected 123–248-kb microduplications in the region of 9p24.3 (chr9: 208454–469022), involving part of or the entire DOCK8 gene. The indications for prenatal diagnosis mainly focused on the risk of maternal serum screening for trisomy 21/18, advanced maternal age, and increased nuchal translucency. No evident structural abnormalities were observed for all fetuses, except for case 5 who presented with increased nuchal translucency in prenatal ultrasound findings. Follow-up of postnatal health was performed and showed no apparent abnormalities for cases 1 to 6 after birth. The parents of case 7 chose to terminate the pregnancy while the parents of case 8 chose to continue the pregnancy. We propose that 9p24.3 microduplications that encompass part of or the entire DOCK8 gene are variants that might be benign. However, further large-scale studies are necessary to evaluate the clinical pathogenicity. For prenatal cases with 9p24.3 microduplication, postnatal health and growth should be followed up and assessed regularly from childhood to adulthood.

Highlights • An 84-year-old Japanese woman with a history of multiple primary meningiomas (PPMs) we first reported. • Histologically confirmed for a right-sided slowly growing lung nodule for 20 years. • Long-term follow-up CT scans reveal multiple lung nodules. • Multiple PPMs are most effectively treated with surgical resection and follow-up examinations. • The tumors prove to be benign by morphology with a relatively long, asymptomatic clinical course., Introduction Primary pulmonary meningiomas (PPMs) are very rare neoplasms, and we reported the first multiple case of PPMs in 1998. Usually, PPMs are slow-growing tumors with a good prognosis. Herein, we reported a rare multiple case of PPMs with an extremely long clinical course. Presentation of the case An 84-year-old Japanese woman with a history of multiple PPMs histologically confirmed as having a right-sided slowly growing lung nodule for 20 years. In 2010, we also reported the additional clinical course in the initial case 10 years after surgery implying a benign biological nature. Subsequent to that report, new lesions appeared in the bilateral lung fields with quite a slow growth rate. She was asymptomatic, and no tumor was observed in the cranial cavity during the course of her disease. Discussion and conclusion This case illustrates rare multiple PPMs and highlights their biological behavior with very slow progression from a most likely benign tumor over a 20-year period.

Background:Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is one of the best-known monogenic auto-inflammatory disorders resulting from an autosomal dominant variation in the TNF super family receptor 1A (TNFRSF1A) gene (1).Objectives:To define best treatment approach in patients with TRAPS and effect on long-term outcomes.Methods:We reviewed all data on patients with TRAPS enrolled in the Eurofever international registry according the INSAID gene variant classification and the new Eurofever/PRINTO classification criteria (EPCC).Results:Data on 226 patients were available. Patients not fulfilling the EPCC carrying likely benign/benign variants (21 patients, 9%) or VOUS/not classified variants (40 patients, 18%) displayed a milder disease than the patients fulfilling the EPCC with VOUS/not classified variants (38 patients, 17%) or pathogenic/likely pathogenic variants (127 patients, 56%). In particular, in patients not fulfilling the EPCC, less frequent abdominal pain and skin rashes, higher efficacy rate of colchicine and no development of AA amyloidosis have been reported. Almost 90% of patients fulfilling the EPCC required maintenance therapy and anti-interleukin (IL)-1 drugs were the most frequently used, with the highest efficacy rate (>85% complete response), while Etanercept was less effectively used and discontinued in 65% of patients.Conclusion:Anti-IL-1 drugs are the best maintenance treatment in TRAPS with potential to reverse the most serious disease complications of AA amyloidosis and infertility. The diagnosis of TRAPS should be considered very carefully in patients carrying VOUS/not classified variants not fulfilling the EPCC.References:[1]Lachmann HJ, Papa R, Gerhold K, Obici L, Touitou I, Cantarini L, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Annals of the rheumatic diseases 2014;73:2160-7.Acknowledgments:RP would like to thank the European Federation of Immunology (EFIS) for the short-term bursary and HL for her continuous support and guidance during the fellowship at the National Amyloidosis Centre in London.Disclosure of Interests:Riccardo Papa: None declared, Thirusha Lane: None declared, Francesca Bovis: None declared, Kirsten Minden Consultant of: GlaxoSmithKline, Sanofi, Speakers bureau: Roche, Isabelle Touitou: None declared, Luca Cantarini: None declared, Marco Cattalini: None declared, Laura Obici: None declared, Annette Jansson: None declared, Alexander Belot: None declared, Beata Woska-Kuśnierz: None declared, Rainer Berendes: None declared, Agustin Remesal: None declared, Marija Jelusic: None declared, Graciela Espada: None declared, Irina Nikishina: None declared, Esther Hoppenreijs: None declared, Maria Cristina Maggio: None declared, Taryn Youngstein: None declared, Tamer Rezk: None declared, Charalampia Papadopoulou: None declared, Paul Brogan Grant/research support from: Roche, Novartis, SOBI, Chemocentryx, Novimmune, Consultant of: Roche, SOBI, UCB, Novartis, Speakers bureau: Roche, SOBI, UCB, Novartis, Philip N Hawkins: None declared, Patricia Woo: None declared, Nicolino Ruperto Grant/research support from: Bristol-Myers Squibb, Eli Lily, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sobi (paid to institution), Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Speakers bureau: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Marco Gattorno Consultant of: Sobi, Novartis, Speakers bureau: Sobi, Novartis, Helen J. Lachmann: None declared

Family studies are an important but underreported source of information for reclassification of variants of uncertain significance (VUS). We evaluated outcomes of a patient-driven framework that offered familial VUS reclassification analysis to any adult with any clinically ascertained VUS from any laboratory in the United States. With guidance from FindMyVariant.org, participants recruited their own relatives for study participation. We genotyped relatives, calculated quantitative cosegregation likelihood ratios, and evaluated variant classifications using Tavtigian’s unified framework for Bayesian analysis with American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. We report participation and VUS reclassification rates from the 50 families enrolled for at least one year and reclassification results for 112 variants from the larger 92-family cohort. For the 50-family cohort, 6.7 relatives per family were invited to participate and 67% of relatives returned samples for genotyping. Sixty-one percent of VUS were reclassified, 84% of which were classified as benign or likely benign. Genotyping relatives identified a de novo variant, phase variants, and relatives with phenotypes highly specific for or incompatible with specific classifications. Motivated families can contribute to successful VUS reclassification at substantially higher rates than those previously published. Clinical laboratories could consider offering family studies to all patients with VUS.

Learning diagnostic labels from image content has been the standard in computer-aided diagnosis. Most computer-aided diagnosis systems use low-level image features extracted directly from image content to train and test machine learning classifiers for diagnostic label prediction. When the ground truth for the diagnostic labels is not available, reference truth is generated from the experts diagnostic interpretations of the image/region of interest. More specifically, when the label is uncertain, e.g. when multiple experts label an image and their interpretations are different, techniques to handle the label variability are necessary. In this paper, we compare three consensus techniques that are typically used to encode the variability in the experts labeling of the medical data: mean, median and mode, and their effects on simple classifiers that can handle deterministic labels (decision trees) and probabilistic vectors of labels (belief decision trees). Given that the NIH/NCI Lung Image Database Consortium (LIDC) data provides interpretations for lung nodules by up to four radiologists, we leverage the LIDC data to evaluate and compare these consensus approaches when creating computer-aided diagnosis systems for lung nodules. First, low-level image features of nodules are extracted and paired with their radiologists semantic ratings (1= most likely benign, , 5 = most likely malignant); second, machine learning multi-class classifiers that handle deterministic labels (decision trees) and probabilistic vectors of labels (belief decision trees) are built to predict the lung nodules semantic ratings. We show that the mean-based consensus generates the most robust classi- fier overall when compared to the median- and mode-based consensus. Lastly, the results of this study show that, when building CAD systems with uncertain diagnostic interpretation, it is important to evaluate different strategies for encoding and predicting the diagnostic label.

Brain malformations are a major cause of therapy-refractory epilepsy as well as neurological and developmental disabilities in children. This study examined the frequency and the nature of copy number variations among children with structural brain malformations and refractory epilepsy. The medical records of all children born between 1990 and 2009 in the epilepsy registry at the Astrid Lindgren's Children's Hospital were reviewed and 86 patients with refractory epilepsy and various brain malformations were identified. Array-CGH analysis was performed in 76 of the patients. Pathogenic copy number variations were detected in seven children (9.2%). In addition, rearrangements of unclear significance, but possibly pathogenic, were detected in 11 (14.5%) individuals. In 37 (48.7%) patients likely benign, but previously unreported, copy number variants were detected. Thus, a large proportion of our patients had at least one rare copy number variant. Our results suggest that array-CGH should be considered as a first line genetic test for children with cerebral malformations and refractory epilepsy unless there is a strong evidence for a specific monogenic syndrome.

Background The 100,000 Genomes Project is a national programme to perform whole genome sequencing (WGS) in families with an undiagnosed rare disorder or cancer. Multiple specialties from GOSH have recruited patients to the pilot study. Here we report on the outcome of the first 111 pilot cases. Methodology Total lymphocyte DNA was extracted (Chemagic Star, Chemagen) and exported to Genomics England for WGS (HiSeqX, Illumina). Prioritised variants were discussed and classified by a multidisciplinary team (MDT) of Clinical Scientists, Consultant Clinical Geneticists and the recruiting clinicians. Variants deemed to be ‘pathogenic’ or ‘likely pathogenic’ were flagged for diagnostic confirmation and clinical reporting. Results Genomics England returned results for 111 cases (probands); 95 (86%) were analysed as trios (proband and both parents). Variant interpretation has been completed for 97 cases (87%). Thirty-six percent of cases (40/111) and a total of 76 variants were discussed at an MDT meeting. Fifty-three percent of variants discussed (40/76) were classified as pathogenic or likely pathogenic, 30% (23/76) were classified as variants of unknown significance and 17% (13/76) were classified as benign or likely benign. This equated to a genetic diagnosis in 27/111 cases (25%) of which 5/111 (5%) were felt to be a partial rather than full explanation of the phenotype. Of the 97 cases where primary analysis was complete, 66/97 (68%) had no primary findings. This included cases in which variants of unknown significance have been detected. Conclusion WGS is a useful tool for rare disease diagnosis especially in patients who have undergone a fruitless diagnostic odyssey. Analysis of GOSH pilot cases has enabled us to develop infrastructure locally to support the return of main programme results. One quarter of GOSH pilot patients should expect a genetic diagnosis from the primary analysis. It is unclear whether this will be an accurate reflection of the diagnostic rate achieved in the main programme due to ongoing refinement of the recruitment and analysis pipelines.

The widespread use of abdominal imaging techniques has increased the detection of solid renal masses over the past years. Imaging plays a crucial role in the management and surveillance and in determining which lesions need treatment. The "classical angiomyolipoma" is the only benign solid renal mass that can be characterized with confidence by imaging through the detection of a fat-containing lesion without calcifications. There is a large overlap of imaging features between benign and malignant renal masses that often makes difficult a correct characterization of these lesions. In this review, we discuss the imaging features of the main solid renal masses that may suggest a likely benign diagnosis.

Among the detected small nodules sized from 3 to 30mm in CT images, a significant portion is undetermined in terms of malignancy which needs biopsy or other follow-up means, resulting in excessive risk and cost. Therefore, predicting the malignancy of the nodules becomes a clinically desirable task. Based on the previous study of texture features extracted from gray-tone spatial-dependence matrices, this study aims to find more efficient texture features or image texture markers in discriminating the nodule malignancy. Two new image texture markers (median and variance) are proposed to classify the small nodules into different malignant levels, thus the risk prediction could be performed through image analysis. These two new image texture markers can minimize the effect of outliers in the feature series, thus can reduce the noise influence to the feature classification. Total 1,353 nodule samples selected from the Lung Image Database Consortium were used to evaluate the efficiency of the proposed new features. All the classification results are shown in the ROC curves and tabulated by the AUC values. The classification outcomes from (1) the most likely and likely benign nodules vs. the most likely and likely malignant nodules, (2) the most likely vs. likely benign nodules, and (3) the most likely vs. likely malignant nodules, are 0.9125±0.0096, 0.9239±0.0147, and 0.8888±0.0197, respectively, in terms of the largest AUC values. From the experimental outcomes on different malignant levels, the two new image texture markers from nodule volumetric CT image data have shown encouraging performance for the risk prediction.

Dancers frequently present to the sports medicine clinic with a variety of lower extremity complaints ranging from acute and traumatic injuries to more chronic, overuse injuries. This case series depicts a similar and unique incidental radiographic finding found in 2 young dancers seen at the same sports medicine clinic. While the findings are likely benign and unrelated to both patients’ initial presentation, the finding of acroosteolysis can be found in more serious systemic and genetic processes as well an early finding in repetitive trauma.

BACKGROUND AND PURPOSE: DWI has been increasingly used to characterize orbital masses and provides quantitative information in the form of the ADC, but studies of DWI of orbital masses have shown a range of reported sensitivities, specificities, and optimal threshold ADC values for distinguishing benign from malignant lesions. Our goal was to determine the optimal use of DWI for imaging orbital masses through aggregation of data from multiple centers. MATERIALS AND METHODS: Source data from 3 previous studies of orbital mass DWI were aggregated, and additional published data points were gathered. Receiver operating characteristic analysis was performed to determine the sensitivity, specificity, and optimal ADC thresholds for distinguishing benign from malignant masses. RESULTS: There was no single ADC threshold that characterized orbital masses as benign or malignant with high sensitivity and specificity. An ADC of less than 0.93 × 10 −3 mm 2 /s was more than 90% specific for malignancy, and an ADC of less than 1.35 × 10 −3 mm 2 /s was more than 90% sensitive for malignancy. With these 2 thresholds, 33% of this cohort could be characterized as “likely malignant,” 29% as “likely benign,” and 38% as “indeterminate.” CONCLUSIONS: No single ADC threshold is highly sensitive and specific for characterizing orbital masses as benign or malignant. If we used 2 thresholds to divide these lesions into 3 categories, however, a majority of orbital masses can be characterized with >90% confidence.

The 2010 consensus statement on diagnostic chromosomal microarray (CMA) testing recommended an array resolution ≥400 kb throughout the genome as a balance of analytical and clinical sensitivity. In spite of the clear evidence for pathogenicity of large copy-number variants (CNVs) in neurodevelopmental disorders and/or congenital anomalies, the significance of small, nonrecurrent CNVs (

Introduction (purpose of the study): The objective of this study was to assess whether dual-time-point ¹⁸F-fluoro-2-deoxyglucose (¹⁸F-FDG)-PET/CT imaging improved the evaluation of suspected malignancy and if there was any resulting change in management. Methods: A total of 53 patients with suspected malignancy were investigated by performing two static acquisitions started at mean times t = 64 and t = 155 min after the tracer injection. The total number of malignant lesions was 133 and the total number of benign lesions was 61. Visual and semiquantitative analysis was performed on both the early and delayed images. Results: Overall, there was a significant improvement (P < 0.001) in the sensitivity of delayed imaging (94%) compared with early imaging (77%) in detecting malignant lesions, without a reduction in specificity. In 10 patients, 13 malignant lesions were undetected on early imaging alone but detected on delayed imaging. In seven patients, 10 malignant lesions were incorrectly classified as 'likely benign' on early imaging but correctly reported as 'likely malignant' on delayed imaging. Management was altered in 2 out of 17 patients. Overall, delayed imaging altered management in 2 out of 53 studied patients. Dual-time-point ¹⁸FDG-PET/CT imaging was useful in differentiating malignant from benign intra-abdominal lesions but did not improve the evaluation of pulmonary lesions. Conclusions:¹⁸F-FDG-PET/CT imaging should be performed as late as reasonably possible after tracer administration in order to increase tumour-to-background contrast and thereby improve the sensitivity of demonstrating additional sites of disease. Dual-time-point ¹⁸FDG-PET/CT may be of benefit in the evaluation of intra-abdominal lesions but does not improve the overall evaluation of pulmonary lesions.

With continued improvement of high-resolution multidetector computed tomography imaging, there is an increasing number of unsuspected thoracic findings. Although many of these findings are of little clinical significance, other findings such as small incidental lung nodules require additional imaging to exclude more worrisome causes, often resulting in greater exposure to ionizing radiation, increased cost, and patient anxiety. Although greater uniformity among radiologists regarding likely benign findings may help reduce unnecessary imaging studies, the lack of clear follow-up guidelines for many findings suggests that further investigation is needed in some areas.

INTRODUCTION The TET2 (Ten‐Eleven Translocation 2) gene, located at chromosome 4q24.1, belongs to TET family of proteins that possesses the capacity of catalyzing the conversion of 5‐methylcytosine into 5‐hydroxymethylcytosine. It is considered to be a putative tumor suppressor gene during cancer initiation and development. TET2 mutations are extensively studied and reported in a variety of human hematological malignancies including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), suggesting a crucial role of TET2 in the pathogenesis of blood cancers. The landscape of rare TET2 variants which may be of potential clinical relevance is not fully described. The landscape of TET2 variants from a large cohort of MDS and AML patients was explored. METHODS We analyzed data from bone marrow samples of 2634 patients with AML or MDS who presented at MD Anderson between the years 2012-2016. Seven hundred seventy seven patients were found to have TET2 variants that were not classifiable as known mutations. Two hundred sixty-three patients were diagnosed with MDS, 144 with secondary AML transformed from MDS, and 370 with AML without prior history of MDS. The coding regions of TET2 gene was analyzed by next-generation sequencing in the molecular diagnostics laboratory. Non-mutation variants were classified into 2 groups: 1) those reported as germline polymorphisms (GP) in population studies, literature or matched tumor-normal analysis on patients at MDACC; and 2) variants for which a germline versus somatic origin could not be determined unequivocally (variants of uncertain origin, VUO). Very common GP variants (defined as those with a population frequency of over 20% in laboratory sample cohort) were not evaluated. Variants' predicted frequency in the population according to gnomAD Exomes 2.0.2, and classification according to American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants, were assessed using the VarSome platform by Saphetor. RESULTS Two-hundred and twenty-eight unique variants were identified. The amino acid substitutions from missense variants were widely distributed throughout TET2. Fifty-four unique variants were classified as GP and several of these recurrent variants were found to be present in our population at a significantly higher frequency (p CONCLUSIONS The landscape of rare TET2 variants in a large group of MDS and AML patients was frequent, diverse, and included both GP and VUO. GP variants were more likely benign by ACMG classification and found in both MDS and AML patients. A large number of singleton VUO were found among MDS patients, and many were predicted to be pathogenic or had uncertain significance. VUO's also contained many fs and nonsense variants. These result support the idea that rare pathogenic variants in TET2 are currently underrecognized as contributory, although they are likely to help drive leukemogenesis. Greater understanding of the importance of individual TET2 variants and additional classification metrics are needed. Disclosures DiNardo: Karyopharm: Honoraria; Abbvie: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Celgene: Honoraria; Bayer: Honoraria. Daver:Karyopharm: Research Funding; Incyte: Consultancy; Novartis: Consultancy; ImmunoGen: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; Alexion: Consultancy; Otsuka: Consultancy; Sunesis: Research Funding; Incyte: Research Funding; ARIAD: Research Funding; BMS: Research Funding; Karyopharm: Consultancy; Novartis: Research Funding; Pfizer: Research Funding. Kadia:Celgene: Research Funding; Takeda: Consultancy; BMS: Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Celgene: Research Funding. Konopleva:Stemline Therapeutics: Research Funding; abbvie: Research Funding; cellectis: Research Funding; Immunogen: Research Funding. Andreeff:Amgen: Consultancy, Research Funding; Astra Zeneca: Research Funding; Jazz Pharma: Consultancy; Oncolyze: Equity Ownership; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; SentiBio: Equity Ownership; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Reata: Equity Ownership; Celgene: Consultancy; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding.

Ophthalmologists may be the first to hear about formed visual hallucinations in the setting of visual loss. Although such hallucinations are likely benign and occur in association with the Charles Bonnet syndrome, it is important to be aware of the strong association of hallucinations with dementia with Lewy bodies because the latter diagnosis is associated with significant prognostic and therapeutic implications for the patient.Single case report.A patient with macular disease was presumed to have formed hallucinations due to the Charles Bonnet syndrome and was subsequently diagnosed with dementia with Lewy bodies after being admitted to a psychiatric facility.Both patients with the Charles Bonnet syndrome and patients with dementia with Lewy bodies can present with formed visual hallucinations. Ophthalmologists and retina specialists, in particular, should be familiar with the features of dementia with Lewy bodies because the diagnosis of this condition can allow appropriate intervention and help prevent drug-related side effects. If there is any suspicion of early dementia in such patients, they may benefit from neuropsychiatric evaluation.

In selected patients, our Unit has recently moved from handheld ultrasound-guided vacuum-assisted core biopsy (VACB) piecemeal acquisition of tissue to the handheld Intact Breast Lesion Excision System (Intact). Intact removes a single piece of tissue, potentially allowing radiologists to excise the entire lesion as well as allowing pathologists to visualise lesion architecture more easily and to calculate margins. We evaluated our early experience of excising benign or likely benign breast lesions using the 20 mm Intact.

Ciliated muconodular papillary tumors (CMPTs) are rare peripheral nodules of the lung first described in 2002. Because of their rarity and nonstandardized diagnostic terminology, CMPTs have been poorly recognized among pathologists. To better characterize these lesions, we undertook a detailed clinicopathologic and immunohistochemical study of 10 archival cases. Ten CMPTs occurred in 7 men and 3 women with a median age of 62 years. All were small peripheral nonendobronchial nodules with a mean diameter of 1.0 cm. All but 1 tumor were incidentally detected by computed tomography-based screening, all of which were radiologically interpreted as adenocarcinomas. Although limited surgery treated all but 1 CMPT, they followed a benign course with no recurrence at a mean follow-up of 43 months (range: 2 to 88 mo). Histologically, CMPTs showed glandular and/or papillary architecture, comprising a vaguely organized mixture of nonatypical ciliated columnar cells, mucous cells, and basal cells, often enveloped by copious intra-alveolar mucin. Micropapillary tufts of ciliated cells and seemingly discontinuous growth along alveolar walls were occasionally present, mimicking adenocarcinomas. Ciliated cells and basal cells were immunopositive for TTF-1 and p40, respectively, whereas mucous cells lacked HNF4α expression. CMPTs are rare, likely benign, underrecognized processes of the lung that should be distinguished from adenocarcinomas.

• Clinical examination of the breast is the weakest test of the “triple diagnostic assessment”, but may be decisive to solve many common symptoms as breast pain, inflammatory changes, acute enlargement of cysts, and many more. • The basic goal of clinical breast examination is to identify a palpable dominant mass, which by definition is a three-dimensional distinct mass that is different from the remainder of the breast tissue and from the tissue of the other breast (not symmetrical). • A dominant breast mass should be definitively diagnosed in a timely manner (old or already recorded, newly or firstly discovered, changing over time, etc.). • Even though a dominant mass in a woman under the age of 40 is most likely benign, a new dominant mass in a postmenopausal woman is most likely malignant.

Purpose To determine the radiological technologist's performance in detecting abnormalities in film-screen mammographic images. Methods Fifty sets of 2-view bilateral mammographic images wereread and judged to be either benign, likely benign, suspicious of abnormality or highly suggestive of malignancy. Seven readers, 5 radiological technologists and 2 radiologists currently working in the field of mammography participated in this study. Results The sensitivity of three-fifths of the technologists in detecting abnormalities that were likely to be a sign of breast cancer was 100%, which was comparable to the 2 participating radiologists. Specificity was also high amongst the technologists, with three-fifths being equal to (88.37%) or better (93.02%) than that of the radiologists (88.37%). Conclusion Of those participating in this study, the findings indicate that the sensitivity and specificity of the majority of individual technologists to detect mammographic abnormalities is comparable to that of the radiologists when compared to the gold standard.

OBJECTIVE. The purpose of this article is to review the imaging features and Liver Imaging Reporting and Data System (LI-RADS) categorization of benign and likely benign entities, including typical cirrhotic nodules, distinctive nodular observations, and benign entities that may simulate hepatocellular carcinoma. CONCLUSION. LI-RADS is a system of standardized criteria for interpreting liver CT and MR images of patients at risk of hepatocellular carcinoma. Most of the observations in these patients are not malignant. With the development of fibrosis and cirrhosis, these benign entities may take on an altered appearance. © American Roentgen Ray Society.

Purpose: To assess the change in diagnostic confidence between first and follow-up dynamic MR examination of the breast (MRM). Methods: The reports of a total of 175 MRM in 77 patients (mean age 50 years; 36-76) with 98 follow-up MRM were analyzed. All examinations were performed as a dynamic study (Gd-DTPA, 0.16 mmol/kg; 6-7 repetitive studies). The change in diagnostic confidence was retrospectively classified as follows: controlled lesion vanished during follow-up (category I); diagnostic confidence increases during follow-up (II), more likely benign (IIa), more suspicious (IIb); no difference in diagnostic confidence (III). Long-term follow-up over an average of four years was obtained for 57 patients with category IIa/III findings. Results: In 98 follow-up examinations, only two lesions vanished (2%). In 77/98 cases a category IIa lesion was diagnosed, in 11 cases a category IIb lesion. In 8 cases (8%) there was no change in diagnostic confidence during follow-up. Lesions in category IIb underwent biopsy in 10/11 cases, in one case long-term follow-up proved a completely regredient inflammatory change. In 8/11 suspicious findings (IIb) a malignant tumor was detected. The mean time interval between first and follow-up MRM was 8 months for I-IIb lesions, and 4 months for category III lesions. In the long-term follow-up two patients with a category IIa lesion developed a carcinoma in a different breast area after four and five years. Conclusion: MRM follow up increases the diagnostic confidence if the time interval is adequate (> 4 months). A persistently or increasingly suspicious finding warrants biopsy.

Infectious and traumatic diseases in the head and neck regions affect many children. Neck lumps in children are more likely benign, and reactive or inflammatory cervical lymphadenopathy is much more common than neoplastic adenopathy. Ultrasound is the first choice of imaging modality for infectious or inflammatory diseases of the neck, whereas plain radiography plays a major role for screening in the traumatic cases. CT, and sometimes MRI, is valuable for more detailed evaluation of the head and neck diseases. In cases of infection involving a specific location in the child’s neck, the possibility of underlying congenital anomalies such as the branchial arch anomaly should be kept in mind for accurate diagnosis.

We experienced a case of malignant pheochromocytoma performed two times of resections for hematogenous metastatic lesions. A 41-year-old woman underwent a left adrenalectomy for a pheochromocytoma which was likely benign. Ten months after the operation, a metastasis to the first lumbar vertebra was found out and a laminectomy was performed. However, another metastasis in the caudate lobe of the liver was diagnosed and the third operation was performed one year and seven months after the left adrenalectomy. The patient died of multiple bone and liver metastase two years and three months after the initial operation.

Enucleation is the preferred surgical management of small, likely benign, insulinomas. Sparing pancreatic parenchyma and minimizing morbidity are of greater importance in these patients due to their anticipated long survival time. Although a laparoscopic approach is ideal, it can be particularly challenging when the insulinoma is retropancreatic or adjacent to critical vascular structures [i.e., superior mesenteric vein-portal vein confluence (SMV-PV)].A 35-year-old woman with neuroglycopenic symptoms and hypoglycemia was diagnosed with hyperinsulinemia. Preoperative CT and EUS-FNA confirmed a 6- × 9-mm neuroendocrine tumor in the parenchyma of the posterior pancreatic neck along the left lateral aspect of the SMV-PV.With the patient in stirrups and arms tucked (French Position), the lesser sac was opened to expose the pancreatic body. A retropancreatic tunnel was created anterior to the SMV-PV and the pancreatic neck encircled with umbilical tape to allow for retraction while minimizing pancreatic manipulation. The insulinoma was definitively identified using intraoperative ultrasound (IOUS). IOUS-guided clip placement facilitated direct identification and permitted safe image-guided enucleation. The enucleation was performed at the parenchymal interface, minimizing the risk of main pancreatic duct injury.Complete pancreatic neck mobilization and view through the laparoscope along the axis of the PV can facilitate exposure at the challenging location of the retropancreatic neck. Transpancreatic IOUS guidance is crucial to identify and safely enucleate small insulinomas in this location. This totally minimally invasive approach can reduce the morbidity of pancreatic surgery for these patients and permit organ-sparing despite the challenging anatomic location.

Follicular patterned lesions of the thyroid are problematic and interpretation is often subjective. While thyroid experts are comfortable with their own criteria and thresholds, those encountering these lesions sporadically have a degree of uncertainty with a proportion of cases. The purpose of this review is to highlight the importance of proper diligent sampling of an encapsulated thyroid lesion (in totality in many cases), examination for capsular and vascular invasion, and finally the assessment of nuclear changes that are pathognomonic of papillary thyroid carcinoma (PTC). Based on these established criteria, an algorithmic approach is suggested using known, accepted terminology. The importance of unequivocal, clear-cut nuclear features of PTC as opposed to inconclusive features is stressed. If the nuclear features in an encapsulated, non-invasive follicular patterned lesion fall short of those encountered in classical PTC, but nonetheless are still worrying or concerning, the term ‘uncertain malignant potential or behaviour, most likely benign’ is suggested. Indubitable, classical PTC nuclei (whether diffuse or restricted to a single high-power field) are diagnostic of a PTC be it classical, non-invasive or invasive follicular variant PTC. Capsular and vascular invasion remain the only reliable predictors of outcome, as non-invasive, encapsulated follicular variant PTC, even with diffuse PTC nuclear change, behaves in an indolent fashion.

Given a predictive model for identifying very likely benign breast lesions on the basis of Breast Imaging Reporting and Data System (BI-RADS) mammographic findings, this study evaluated the model's ability to generalize to a patient data set from a different institution.The artificial neural network model underwent three trials: it was optimized over 500 biopsy-proven lesions from Duke University Medical Center or "Duke," evaluated on 1,000 similar cases from the University of Pennsylvania Health System or "Penn," and reoptimized for Penn.Trial A's Duke-only model yielded 98% sensitivity, 36% specificity, area index (A(z)) of 0.86, and partial A(z) of 0.51. The cross-institutional trial B yielded 96% sensitivity, 28% specificity, A(z) of 0.79, and partial A(z) of 0.28. The decreases were significant for both A(z) (p = 0.017) and partial A(z) (p0.001). In trial C, the model reoptimized for the Penn data yielded 96% sensitivity, 35% specificity, A(z) of 0.83, and partial A(z) of 0.32. There were no significant differences compared with trial B for specificity (p = 0.44) or partial A(z) (p = 0.46), suggesting that the Penn data were inherently more difficult to characterize.The BI-RADS lexicon facilitated the cross-institutional test of a breast cancer prediction model. The model generalized reasonably well, but there were significant performance decreases. The cross-institutional performance was encouraging because it was not significantly different from that of a reoptimized model using the second data set at high sensitivities. This study indicates the need for further work to collect more data and to improve the robustness of the model.

Objectifs pedagogiques By the end of this lecture we should to be able to understand normal breast anatomy, and both benign and malignant processes as they relate to traditional imaging signs and pathologic changes. Masses and calcifications will be stressed. Messages a retenir The mass edge represents the aggressiveness of the underlying abnormality. By analyzing the mass edge we can determine the likely benign or malignant nature of the mass. Malignant masses have microlobulated, spiculated and indistinct edges while benign masses have smooth or mildly lobulated circumscribed edges. The shape of the calcification represents a cast of an underling space. Benign spaces in the breast are smooth, round or tubular shaped, yielding smooth round and smooth rod shaped calcifications. Malignant processes show irregular growth and necrosis, giving irregular shaped calcifications.

A CASE OF benign duodenocolic fistula is presented chiefly because of its rarity, it being the eighth recorded case in the literature covering the period since 1885. It is interesting that seven of the eight patients reported on have survived operation and recovered. The first case, reported by Rees1in 1933, was that of a duodenocolic fistula associated with an incompetent sphincter of Oddi. It was thought that the fistula developed as a result of perforation from a typhoid ulcer 28 years previously. Recovery was complete after operation. McPeak2reported two cases in 1940. The first patient survived for six years after closure of the fistula. Though no tissue was removed for microscopic examination, the lesion was likely benign. The second patient died on the twelfth postoperative day from peritonitis. Autopsy confirmed the clinical impression of a benign fistula. It was thought that both patients had had a

To the Editor.— In a recent letter, 1 the roles of the physicians attending Frederick III were presented in a maneuver that seems not entirely supported by sources closest to the issues and events themselves. In discussing Virchow's role in the treatment of Frederick III, emperor of the German Republic, Dr deR Kolisch states that "British surgeons" diagnosed the Crown Prince's laryngeal lesion as cancer, while Virchow "booted the diagnosis." In point of fact, it was the German surgeons who made this diagnosis and proposed surgical treatment for the lesion. The German royal family, no doubt influenced by their relatives among the British royalty, obtained an independent opinion from Morell Mackenzie, a British laryngologist. It was Mackenzie, not the Germans, who suggested that the disease was more likely benign. Mackenzie nevertheless performed a biopsy of the lesion, and, according to Virchow, these tissue specimens did not support a diagnosis of