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Background: Serum biomarkers for diagnosis and risk stratification of childhood solid tumors would improve the accuracy/timeliness of diagnosis and reduce the need for invasive biopsies. We hypothesized that differential expression and/or release of microRNAs (miRNAs) by such tumors may be detected as altered serum miRNA profiles.Methods: We undertook global quantitative reverse transcription PCR (qRT-PCR) miRNA profiling (n = 741) on RNA from 53 serum samples, representing 33 diagnostic cases of common childhood cancers plus 20 controls. Technical confirmation was performed in a subset of 21 cases, plus four independent samples.Results: We incorporated robust quality control steps for RNA extraction, qRT-PCR efficiency and hemolysis quantification. We evaluated multiple methods to normalize global profiling data and identified the ‘global mean’ approach as optimal. We generated a panel of six miRNAs that were most stable in pediatric serum samples and therefore most suitable for normalization of targeted miRNA qRT-PCR data. Tumor-specific serum miRNA profiles were identified for each tumor type and selected miRNAs underwent confirmatory testing. We identified a panel of miRNAs (miR-124-3p/miR-9-3p/miR-218-5p/miR-490-5p/miR-1538) of potential importance in the clinical management of neuroblastoma, as they were consistently highly overexpressed in MYCN-amplified high-risk cases (MYCN-NB). We also derived candidate miRNA panels for noninvasive differential diagnosis of a liver mass (hepatoblastoma vs. combined MYCN-NB/NB), an abdominal mass (Wilms tumor vs. combined MYCN-NB/NB), and sarcoma subtypes.Conclusions: This study describes a pipeline for robust diagnostic serum miRNA profiling in childhood solid tumors, and has identified candidate miRNA profiles for prospective testing.Impact: We propose a new noninvasive method with the potential to diagnose childhood solid tumors. Cancer Epidemiol Biomarkers Prev; 24(2); 350–60. ©2014 AACR.

Supplementary Materials, Tables S1 and S2, Figures S1-S10. Supplementary Table S1. Number of over-expressed serum microRNAs in solid tumor types of childhood. Supplementary Table S2. Ten over-expressed serum microRNAs selected for the technical confirmation qRT-PCR study. Supplementary Table and Figure Legends, Supplementary References. Supplementary Figure S1. Quality control (QC) assessments in the initial qRT-PCR run. Supplementary Figure S2. Confirmation of suitability of the four serum QC housekeeping microRNAs for screening samples for the full discovery-phase qRT-PCR run. Supplementary Figure S3. QC assessments in the full discovery-phase qRT-PCR run. Supplementary Figure S4. Hemolysis assessment of the 53 serum samples in the initial QC and full discovery-phase qRT-PCR run. Supplementary Figure S5. Further QC assessment of the 53 serum samples in the full discovery-phase qRT-PCR run. Supplementary Figure S6. Top-ranking overlapping housekeeping microRNAs identified by NormFinder and geNorm algorithms, suitable for targeted serum qRT-PCR studies. Supplementary Figure S7. Comparison of expression of miR-122-3p and miR-122-5p in the 53 serum samples in the full discovery-phase qRT-PCR run. Supplementary Figure S8. Comparison of the average raw Ct values in the 21 serum samples common to both the full discovery-phase and technical confirmation qRT-PCR run. Supplementary Figure S9. QC assessment in the technical confirmation qRT-PCR run for all 25 serum samples used. Supplementary Figure S10. Serum microRNA expression in osteosarcoma.

Supplementary Tables S3 to S13. Over-expressed serum microRNAs in individual types of solid tumor of childhood. The Tables list the over-expressed microRNAs in individual types of solid tumor of childhood compared with the 'other tumor' group and control group, their fold-changes, coefficient of variation and robust rank aggregate (RRA) score. Key: FC =fold-change; CV = coefficient of variation. Table S3: MYCN-amplified INRG high-risk neuroblastoma (MYCN-NB). Table S4: non-MYCN-amplified INRG low-risk neuroblastoma (NB). Table S5: mhepatoblastoma(HB). Table S6: Wilms tumor (WT). Table S7 = rhabdomyosarcoma (RMS). Table S8: Ewings sarcoma (ES). Table S9: osteosarcoma (OS). Table S10: B-cell non-Hodgkin's lymphoma (BNHL). Table S11: Hodgkin's disease (HD). Table S12: pleuropulmonary blastoma (PPB) Table S13: Central nervous system glioma (GL).

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Supplementary Methods from Pediatric Malignant Germ Cell Tumors Show Characteristic Transcriptome Profiles

PDF - 62K, Supplementary Table 1: Clinico-pathological data for sample set-3. Supplementary Table 2: Primers used for mRNA qRT-PCR. Supplementary Table 3: Expression of let-7 family microRNAs in pediatric malignant-GCTs. Supplementary Table 4: Let-7 mRNA targets identified in combined microarray analysis of pediatric and adult malignant-GCTs. Supplementary Table 5: The six let-7 mRNA targets selected following microarray and qRT-PCR analysis.

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Supplementary Figure 1 from Pediatric Malignant Germ Cell Tumors Show Characteristic Transcriptome Profiles

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Supplementary Figure 8 from Pediatric Malignant Germ Cell Tumors Show Characteristic Transcriptome Profiles

Supplementary Figure 5 from Pediatric Malignant Germ Cell Tumors Show Characteristic Transcriptome Profiles

Supplementary Figure 7 from Pediatric Malignant Germ Cell Tumors Show Characteristic Transcriptome Profiles

Malignant germ cell tumors (GCT) of childhood are rare and heterogeneous neoplasms thought to arise from primordial germ cells. They vary substantially in their natural history and show important clinical differences from their adult counterparts. To address the biological basis for these observations, we have undertaken a comprehensive analysis of global gene expression patterns in pediatric malignant GCTs and compared these findings with published data on adult testicular GCTs (TGCT). Our study included 27 primary tumors and assessed the principal malignant histologic types of pediatric GCT, yolk sac tumor (YST; n = 18), and seminoma (n = 9). Analysis of Affymetrix U133A GeneChip data was performed using the statistical software environment R, including gene set enrichment analysis, with cross-validation at the RNA and protein level. Unsupervised analysis showed complete separation of YSTs and seminomas by global gene expression profiles and identified a robust set of 657 discriminatory transcripts. There was no segregation of tumors of the same histology arising at different sites or at different ages within the pediatric range. In contrast, there was segregation of pediatric malignant GCTs and adult malignant TGCTs, most notably for the YSTs. The pediatric seminomas were significantly enriched for genes associated with the self-renewing pluripotent phenotype, whereas the pediatric YSTs were significantly enriched for genes associated with a differentiation and proliferation phenotype. We conclude that histologic type is the key discriminator in pediatric malignant GCTs and that the observed clinical differences between malignant GCTs of children and adults are mirrored by significant differences in global gene expression. [Cancer Res 2008;68(11):4239–47]

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Supplementary Figure 4 from Pediatric Malignant Germ Cell Tumors Show Characteristic Transcriptome Profiles

PDF - 492K, Supplementary Figure 1: Levels of the nine members of the let-7 family in pediatric malignant-GCTs. Supplementary Figure 2: PCR quantification of let-7e, LIN28 and LIN28B in malignant-GCTs.Supplementary Figure 3: Sylamer analysis of up-regulated genes in pediatric and adult malignant-GCTs. Supplementary Figure 4: Correlations between levels of let-7 and mRNA targets. Supplementary Figure 5: PCR quantification of HMGA2 in pediatric malignant-GCTs. Supplementary Figure 6: PCR validation of expression of selected let-7 mRNA targets in pediatric malignant-GCTs. Supplementary Figure 7: Effects of LIN28 depletion in malignant-GCT cells. Supplementary Figure 8: Independent confirmation of specific effects of LIN28 depletion in malignant-GCT cells. Supplementary Figure 9: Effects of let-7e mimic in malignant-GCT cells. Supplementary Figure 10: Relationships between MYCN and C-MYC versus LIN28 and LIN28B in malignant-GCTs. Supplementary Figure 11: MYCN depletion in malignant-GCTs (S11). Supplementary Figure 12: Schematic of the LIN28/let-7 axis in malignant-GCTs.

Germ cell tumours (GCTs) are a heterogeneous group of rare neoplasms that present in different anatomical sites and across a wide spectrum of patient ages from birth through to adulthood. Once these strata are applied, cohort numbers become modest, hindering inferences regarding management and therapeutic advances. Moreover, patients with GCTs are treated by different medical professionals including paediatric oncologists, neuro-oncologists, medical oncologists, neurosurgeons, gynaecological oncologists, surgeons, and urologists. Silos of care have thus formed, further hampering knowledge dissemination between specialists. Dedicated biobank specimen collection is therefore critical to foster continuous growth in our understanding of similarities and differences by age, gender, and site, particularly for rare cancers such as GCTs. Here, the Malignant Germ Cell International Consortium provides a framework to create a sustainable, global research infrastructure that facilitates acquisition of tissue and liquid biopsies together with matched clinical data sets that reflect the diversity of GCTs. Such an effort would create an invaluable repository of clinical and biological data which can underpin international collaborations that span professional boundaries, translate into clinical practice, and ultimately impact patient outcomes., St Baldrick's Foundation

Analyses of small non-coding RNA (ncRNA) expression in malignant germ cell tumours (GCTs) have focused on microRNAs (miRNAs). As GCTs all arise from primordial germ cells, and piwi-interacting RNAs (piRNAs) have important roles in maintaining germline integrity via transposon silencing, we hypothesised that malignant GCTs are characterised by fundamental piRNA dysregulation.We undertook global small ncRNA sequencing in malignant GCTs, in order to describe small ncRNA expression changes for both miRNAs and piRNAs.We performed small ncRNA next generation sequencing on a representative panel of 47 samples, comprising malignant GCT (n = 31) and control (n = 16) tissues/cell lines. Following quality control and normalisation, filtered count reads were used for differential miRNA and piRNA expression analyses via DESeq2. Predicted mRNA targets for piRNAs were identified and utilised for pathway enrichment analyses.Overall, miRNAs and piRNAs comprised 21.9% and 43.0% of small ncRNA species, respectively. There were 749 differentially expressed miRNAs in malignant GCTs, of which 536 (72%) were over-expressed and 213 (28%) under-expressed. The top-ranking over-expressed miRNAs were exclusively from the miR-371∼373 and miR-302/367 clusters. The most significantly under-expressed miRNAs were miR-100-5p, miR-214-3p, miR-125b-5p and let-7 family members, including miR-202-3p. There were 1,121 differentially expressed piRNAs in malignant GCTs, of which 167 (15%) were over-expressed and 954 (85%) under-expressed. Of note, of the top-20 differentially expressed piRNAs, 16 were over-expressed, of which piR-hsa-2506793 was both top-ranking and most abundant. Mobile element (ME; i.e., transposon)-associated piRNAs comprised 166 (15%) of the 1,121 differentially expressed piRNAs, of which 165 (99%) were down-regulated. The remaining 955 (85%) non-ME-associated piRNAs may have wider cellular roles. To explore this, predicted mRNA targets of differentially expressed piRNAs identified putative involvement in cancer-associated pathways.This study confirms previous miRNA observations, giving credence to our novel demonstration of global piRNA dysregulation in gonadal malignant GCTs, through both ME and non-ME-associated pathways, which likely contributes to GCT pathogenesis.

Background: CNS germinoma, being marker-negative, are mainly diagnosed by histological examination. These tumors predominantly appear in the suprasellar and/or pineal region. In contrast to the suprasellar region, where biopsy is the standard procedure in case of a suspected germ-cell tumor to avoid mutilation to the endocrine structures, pineal tumors are more accessible to primary resection. We evaluated the perioperative course of patients with pineal germinoma who were diagnosed by primary biopsy or resection in the SIOP CNS GCT 96 trial. Methods: Overall, 235 patients had germinoma, with pineal localization in 113. The relationship between initial symptoms, tumor size, and postoperative complications was analyzed. Results: Of 111 evaluable patients, initial symptoms were headache (n = 98), hydrocephalus (n = 93), double vision (n = 62), Parinaud syndrome (n = 57), and papilledema (n = 44). There was no significant relationship between tumor size and primary symptoms. A total of 57 patients underwent primary resection and 54 underwent biopsy. Postoperative complications were reported in 43.2% of patients after resection and in 11.4% after biopsy (p < 0.008). Biopsy was significantly more commonly performed on larger tumors (p= 0.002). Conclusions: These results support the practice of biopsy over resection for histological confirmation of pineal germinoma.

Homogeneous and common objective disease assessments and standardised response criteria are important for better international clinical trials for CNS germ cell tumours. Currently, European protocols differ from those of North America (the USA and Canada) in terms of criteria to assess radiological disease response. An international working group of the European Society for Paediatric Oncology Brain Tumour Group and North American Children's Oncology Group was therefore established to review existing literature and current practices, identify major challenges regarding imaging assessment, and develop consensus recommendations for imaging response assessment for patients with CNS germ cell tumours. New clinical imaging standards were defined for the most common sites of CNS germ cell tumour and for the definition of locoregional extension. These new standards will allow the evaluation of response to therapy in patients with CNS germ cell tumours to be more consistent, and facilitate direct comparison of treatment outcomes across international studies.

Whole-genome sequencing (WGS) of cancers is becoming an accepted component of oncological care, and NHS England is currently rolling out WGS for all children with cancer. This approach was piloted during the 100,000 genomes (100 K) project. Here we share the experience of the East of England Genomic Medicine Centre (East-GMC), reporting the feasibility and clinical utility of centralised WGS for individual children locally.Non-consecutive children with solid tumours were recruited into the pilot 100 K project at our Genomic Medicine Centre. Variant catalogues were returned for local scrutiny and appraisal at dedicated genomic tumour advisory boards with an emphasis on a detailed exploration of potential clinical value.Thirty-six children, representing one-sixth of the national 100 K cohort, were recruited through our Genomic Medicine Centre. The diagnoses encompassed 23 different solid tumour types and WGS provided clinical utility, beyond standard-of-care assays, by refining (2/36) or changing (4/36) diagnoses, providing prognostic information (8/36), defining pathogenic germline mutations (1/36) or revealing novel therapeutic opportunities (8/36).Our findings demonstrate the feasibility and clinical value of centralised WGS for children with cancer. WGS offered additional clinical value, especially in diagnostic terms. However, our experience highlights the need for local expertise in scrutinising and clinically interpreting centrally derived variant calls for individual children.

Chapter two explains the shutdown of racing in New York following the passage of a series of anti-gambling laws pushed by governor Charles Evans Hughes amid a national wave of Progressive Era reform. With racing banned in all but a few American jurisdictions in the early twentieth century, leading owners sent their stock to Europe. Jockeys and trainers followed. The glut of American horses flooding Great Britain sewed animosity between horsemen of the two nations. With the onset of World War I, American equestrians began a mass exodus back to the states, though resentments remained. Upon the war's conclusion, American racing would enjoy a period of rebirth as the political pendulum moved away from the Progressive spirit that had dominated American politics in the first two decades of the twentieth century and back toward a laissez-faire ethos.

On October 20, 1923, at Belmont Park in New York, Kentucky Derby champion Zev toed the starting line alongside Epsom Derby winner Papyrus, England's top three-year-old colt. Few happenings had ever been covered so closely by American newspapers as the spectacle officially dubbed the International Race. The extraordinary hype surrounding the event was even more notable considering that only a few years earlier Thoroughbred racing had been on the brink of Progressive-era extinction in the United States. But following a post-World War I political sea change in the United States, in what would later be remembered as a "golden age" of sport, Americans rallied around the horse that was, in the words of its owner Harry F. Sinclair, "racing for America," while Sinclair was engaged in a scheme to defraud the United States of millions of barrels of publicly owned oil in one of the most notorious instances of political corruption in American history -- the Teapot Dome scandal. America First examines the postwar revival of American horseracing, culminating in the intercontinental showdown between Zev and Papyrus, that captured some of the incongruity and contradiction of 1920s America.

Chapter Seven covers the fallout from the Race of the Century. After being embraced as "magnificent losers" in America, team Papyrus returned home to a disappointed nation full of critics of the entire endeavor. The score between Zev and My Own was settled by another blockbuster event, at Latonia Race Track. Nationally, promoters capitalized on the publicity of the International Race to build support for the expansion of horseracing and legalized gambling. With his triumph in the International Race, Earl Sande had reached the height of sports celebrity. But personal and professional challenges mounted, and he would die in an Oregon nursing home, nearly forgotten by the sports industry that had made him famous. Though Sinclair's acquittal on federal bribery charges related to his Teapot Dome scheme would shock many observers, he served nearly seven months in the Washington Asylum and Jail for contempt of the Senate and jury tampering.

Chapter Six describes the scene surrounding the International Race. New York was abuzz with anticipation, and newspaper readers across America received daily updates from Belmont Park. Thousands of New Yorkers made their first trip to the races despite two days of rain that had rendered the track a soupy mess. English trainer Basil Jarvis's decision not to shoe his horse in footwear designed for mud probably doomed Papyrus's chances. Zev's five-length win thrilled American fans. But given the hardships endured by his opponent, the result felt a bit hollow to some, as though there had been more sizzle than substance to the whole affair. With the victory, jockey Earl Sande exorcised memories of past failures in big races and established himself as the sport's greatest rider as horseracing continued its dramatic resurgence toward mainstream popularity.

Chapter Five discusses the origins of the International Race and the British contestants' transatlantic voyage to America. August Belmont II, chairman of the powerful Jockey Club in New York, convinced Benjamin Irish, the farmer and caterer of relatively modest means who owned Epsom Derby winner Papyrus, to agree to a match race against a to-be-determined American horse. Kentucky Derby champion Zev was the likeliest choice. Admiral Cary T. Grayson, friend and physician to former president Woodrow Wilson, owned the other leading American candidate, My Own. But Hildreth and Sinclair manipulated the selection process. Newspaper coverage of the procedural gamesmanship helped to hype the event. Sportswriters' profiles of the men associated with the English horse -- including jockey Steve Donoghue, who had risen from a rough industrial town to become the most famous rider in the world, and a modest second-generation Newmarket trainer named Basil Jarvis -- spread the ballyhoo nationwide.

On October 20, 1923, at New York's Belmont Park, Kentucky Derby champion Zev toed the starting line alongside Papyrus, winner of England's greatest horse race, the Epsom Derby. The $100,000 purse for the novel intercontinental showdown was the largest in the history of America's oldest sport and writers across the country were calling it the "Race of the Century." A victory for the American colt in this blockbuster event would change how the nation viewed horse racing forever. In this book, James C. Nicholson exposes the central role of politics, money, and ballyhoo in the Jazz Age resurgence of the sport of kings. Though the Zev-Papyrus face-off was one of the most hyped sporting events of the early twentieth century, Nicholson reveals that it soon faded from American popular memory when it became known that Zev's owner, oil tycoon Harry F. Sinclair, was involved in an infamous scandal to defraud the United States of millions of barrels of publicly owned oil. As a result, Zev became an apt mascot for a nation struggling to reconcile its traditional values with the modern complexities of the Roaring Twenties, and his tainted legacy ultimately proved to be incompatible with tenets of national mythology that celebrate America as a place where hard work and fair play lead to prosperity.

Chapter three describes Harry F. Sinclair's remarkable run of success in the Mid-continent oil fields that allowed him to plow some of his vast profits into sports ventures, including ownership of a Federal League baseball team. In 1919, Sinclair purchased Rancocas Farm in New Jersey, once owned by tobacco manufacturing heir Pierre Lorillard, whose Thoroughbred Iroquois was the first American horse to win England's greatest horse race, the Epsom Derby. Sinclair spared no expense in building the most formidable racing stable in America, with the help of the embattled trainer Sam Hildreth. As Sinclair entered the racing scene, the sport's great equine hero was Man o' War, whose dazzling performances in a two-year racing career ending in 1920 set a new standard for excellence which Sinclair hoped to exceed.

Chapter four explores Harry Sinclair's involvement in the notorious Teapot Dome oil scandal. Republican Warren G. Harding's landslide victory in the 1920 presidential election marked a new direction in American politics, ending the Progressive Era and ushering in a pro-business climate that would further enrich men like Sinclair and facilitate the return of American horseracing to national prominence. New secretary of the interior Albert B. Fall transferred oil reserves held by the US Navy in Wyoming to Sinclair. As news of the shady deal spread, Sinclair debuted his colt Zev, named after the oilman's attorney, William Zevely, who was a facilitator of the corrupt bargain. Zev would surpass Man o' War's all-time American earnings record, and his twenty-three career wins would include scores in the Kentucky Derby, Belmont Stakes, and the Race of the Century against English champion Papyrus.

Germ-cell tumours (GCT) comprise a heterogeneous group of tumours, occurring mainly in children, adolescents, and young adults, which vary by site, range of histological subtypes, and behaviour. Gonadal sites, testes, and ovaries account for around two thirds of extracranial GCT, the remainder occurring at extragonadal sites. Histological components range from mature benign teratoma to malignant subtypes, germinoma, yolk sac tumour, choriocarcinoma, and embryonal carcinoma. Raised levels of the tumour marker alphafetoprotein (AFP) in yolk sac tumours, and human chorionic gonadotrophin (HCG) in choriocarcinoma and, to lower levels, in germinoma/dysgerminoma/semi-noma, assist with diagnosis and are useful for monitoring response to treatment and in follow-up. Genomic and transcriptomic analysis provide some insight into the nature of GCT, with common patterns of chromosomal imbalance identified, and distinguish between adult and paediatric GCT with respect to their messenger RNA-expression patterns. Patterns of microRNA expression, common to malignant GCT, across all age groups and histological subtypes, have also been identified in both tumour and serum, where they have potential for use in non-invasive diagnostics and monitoring. Management of teratoma is surgical, and completely resected stage 1 malignant GCT can also be managed with resection followed by close observation. Higher-stage malignant tumours warrant adjunctive chemotherapy following diagnosis. Unresectable tumours may be managed with neoadjuvant chemotherapy and delayed resection. Chemotherapy strategies employ platinum-containing combinations. Outcomes are excellent in the majority of cases, so the goal of new treatment strategies is mainly focused on minimizing late effects of treatment. Many relapses can be salvaged with further chemotherapy.

Uday Jammalamadaka,1 Karthik Tappa,1 Jeffery A Weisman,1 James Connor Nicholson,2 David K Mills1,3 1Center for Biomedical Engineering and Rehabilitation Science, 2Nanosystems Engineering, 3The School of Biological Sciences, Louisiana Tech University, Ruston, LA,USA Abstract: Halloysite nanotubes (HNTs) were investigated as a platform for tunable nanoparticle composition and enhanced opacity in poly(methyl methacrylate) (PMMA) bone cement. Halloysite has been widely used to increase the mechanical properties of various polymer matrices, in stark contrast to other fillers such as barium sulfate that provide opacity but also decrease mechanical strength. The present work describes a dry deposition method for successively fabricating barium sulfate nanoparticles onto the exterior surface of HNTs. A sintering process was used to coat the HNTs in barium sulfate. Barium sulfate-coated HNTs were then added to PMMA bone cement and the samples were tested for mechanical strength and tailored opacity correlated with the fabrication ratio and the amount of barium sulfate-coated HNTs added. The potential cytotoxic effect of barium-coated HNTs in PMMA cement was also tested on osteosarcoma cells. Barium-coated HNTs were found to be completely cytocompatible, and cell proliferation was not inhibited after exposure to the barium-coated HNTs embedded in PMMA cement. We demonstrate a simple method for the creation of barium-coated nanoparticles that imparted improved contrast and material properties to native PMMA. An easy and efficient method for coating clay nanotubes offers the potential for enhanced imaging by radiologists or orthopedic surgeons. Keywords: barium, bone cement, halloysite, imaging, PMMA, sintering

Germ cell tumours (GCTs) comprise a heterogeneous group of tumours believed to arise from the totipotent primordial germ cell. While uncommon, they may present at any age from in-utero to young adulthood. Prognosis is generally good and considering them in the differential diagnosis of midline as well as gonadal masses may prevent diagnostic delay and/or escalation of potentially harmful treatment. In childhood, approximately 50% are gonadal and 50% extragonadal (20% intracranial/30% extracranial). Clinical presentation relates to mass effect at tumour site. Teratomas account for 50% of paediatric GCTs and, whilst considered benign, may recur if not completely excised. Malignant GCTs often secrete the tumour markers alpha-fetoprotein and human chorionic gonadotrophin, which may help in diagnosis and follow-up. Outcomes are generally good with >90% five-year overall survival. Management involves complete surgical resection for teratomas and non-metastatic gonadal tumours. In the UK, chemotherapy is reserved for stage 2–4 extracranial malignant GCTs. Intracranial tumours typically occur in the midline in the pineal and/or suprasellar regions. Intracranial germinomas are cured in >90% cases with radiotherapy or combined chemo-radiotherapy. About two-thirds of non-germinomatous intracranial tumours are cured with combined chemo-radiotherapy. Current issues relating to the diagnosis and management of teenagers and young adults with GCTs are highlighted.

We aimed to retrospectively assess treatments/outcomes, including the value of high-dose-chemotherapy and autologous-stem-cell-rescue (HDC + AuSCR) and re-irradiation, in a large, European patient-cohort with relapsed intracranial germ-cell-tumors (GCTs) receiving uniform first-line therapy, including radiotherapy as standard-of-care. Fifty-eight UK/German patients (48 male/10 female) with relapsed intracranial-GCTs [13 germinoma/45 non-germinomatous GCT (NGGCT)] treated 1996-2010 as per the SIOP-CNS-GCT-96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five-year overall-survival (OS) for the whole-group (n = 11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard-dose-chemotherapy (SDC) and re-irradiation or HDC + AuSCR with/without re-irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (three non-protocol adherence, five teratoma, five palliation). Five-year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9% (95%CI: 2-26%). By treatment received, 5-year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC + AuSCR was 0% (0-0%) and 14% (3-36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5-year OS than those with relapsed NGGCT (55 vs. 9%; p = 0.007). Patients with relapsed germinoma were salvaged both with SDC and re-irradiation or HDC + AuSCR with/without re-irradiation; both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa-based HDC + AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery/irradiation where feasible.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young women. SCCOHT has recently been identified as a monogenic disorder caused by germline and/or somatic SMARCA4 mutations. We describe a 15-year-old Caucasian female with a SCCOHT harboring a previously unreported somatic mutation in the SMARCA4 gene (c.1757delA; p.K586.fs) with loss of heterozygosity. No germline mutation was identified. Subsequent immunohistochemical staining confirmed loss of SMARCA4 protein. These molecular findings will aid with SCCOHT diagnosis through immunohistochemical staining for SMARCA4 and in the future may have implications for the management of this disease.