Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a deletion of ∼400 kb in chromosome 19, resulting in a fusion of the genes for the heat shock protein, DNAJ (Hsp40) homolog, subfamily B, member 1, DNAJB1, and the catalytic subunit of protein kinase A, PRKACA. The resulting chimeric transcript produces a fusion protein that retains kinase activity. No other recurrent genomic alterations have been identified. Here we characterize the molecular pathogenesis of FLHCC with transcriptome sequencing (RNA sequencing). Differential expression (tumor vs. adjacent normal tissue) was detected for more than 3,500 genes (log2 fold change ≥1, false discovery rate ≤0.01), many of which were distinct from those found in hepatocellular carcinoma. Expression of several known oncogenes, such as ErbB2 and Aurora Kinase A, was increased in tumor samples. These and other dysregulated genes may serve as potential targets for therapeutic intervention.

fibrolamellar carcinoma drug repurposing pediatric rare tumors patient derived xenografts drug screening fusion gene Abbreviations: ATR -Ataxia telangiectasia and Rad3-related protein AURKA -Aurora kinase A AURKB -Aurora kinase B Bcl-xL -B-cell lymphoma-extra large encoded by the BCL2-like 1 gene Bcl2 -B-cell lymphoma 2 ITS -Insulin, (human) Transferrin, Selenium BID -BH3 Interacting Domain Death Agonist BIM -Bcl-2-like protein 11 CA12 -Carbonic anhydrase 12 CDc7 -Cell division cycle 7-related protein kinase CDK -Cyclin depedent protein kinase Cyp19A1 -Also know as aromatase or estrogen synthase DAB -3,3'-Diaminobenzidine DMSO -Dimethyl sulfoxide DNA-PK -DNA protein kinase EGFR -Epidermal growth factor receptor eIF4F -Eukaryotic initiation factor 4F ErbB2 -erythroblastic oncogene B, also known as Her-2 protooncogene Neu and as epidermal growth factor receptor-2 FLC -fibrolamellar hepatocellular carcinoma H&E -hematoxylin and eosin HSA -Highest Single Agent HCC -hepatocellular carcinoma HDAC -Histone deacetylase HSP70 -Heat Shock Protein 70

Fibrolamellar hepatocellular carcinoma is a rare primary liver tumor that often arises in the absence of cirrhosis or viral hepatitis. Compared with hepatocellular carcinoma, patients are typically younger with less comorbidities. Diagnosis is often multimodal and requires a high level of suspicion, as traditional liver pathology markers, such as serum ? fetoprotein and transaminases, are often normal. Overall, patients respond well to surgical resection but recurrences are frequent, and alternative therapies, such as chemotherapy and radiation, are not well studied. Currently, there are no established chemotherapy regimens; there are only limited case reports of select agents, such as 5-fluorouracil with interferon-? and gemcitabine with oxaliplatin, used with varying degrees of success. Because little is known about this rare tumor, the development of serum markers and alternative therapies continues to be a challenge. A major advancement in the understanding of this rare disease is the discovery of a functional chimeric transcript incorporating DNAJB1 and PRKACA. This finding may finally provide the basis for specific diagnostic markers and chemotherapies that patients with this disease have long needed. Here, we present advances in the surgical treatment of fibrolamellar hepatocellular carcinoma, as well as recent data on its tumor biology and pathogenesis.

Purpose Cooperative studies support complete metastasectomy in osteosarcoma (OS). Pre-operative CT is used to identify and quantify metastases and can facilitate minimally invasive techniques. Here we assess the accuracy of pre-operative CT compared to findings at thoracotomy and its change over time. Methods We reviewed OS thoracotomies performed at our institution from 1996-2015. The number of metastases identified on pre-operative chest CT was compared to the number of metastases seen on pathology (both metastases with viable cells and non-viable, osteoid-only metastases). Results Eighty-eight patients underwent 161 thoracotomies with a median of 14 days (range, 1-85) between CT and surgery, a median of 2 CT-identified lesions (range, 0-15), and a median of 4 resected lesions (range, 1-25). In 56 (34.8%) cases, more metastases were found surgically than were seen on CT, and among these, 34 (21.1%) had a greater number of viable metastases. There was poor overall correlation between CT and pathology findings (Kendall Tau-b = 0.506), regardless of CT slice thickness, decade of thoracotomy, or total number of CT-identified lesions. Conclusions CT accuracy in pre-operatively quantifying OS pulmonary metastases has not improved in recent decades. Consequently, we recommend an open technique with direct lung palpation for complete identification and resection of OS pulmonary metastases.

Introduction Non-central nervous system (non-CNS) rhabdoid tumors tend to present at a young age and have an extremely aggressive course, with dismal overall survival rates. Inactivation of the tumor suppressor gene SMARCB1 has been shown in rhabdoid tumors regardless of anatomic location, suggesting a common genetic basis. We retrospectively analyzed our institutional experience with non-CNS rhabdoid tumors to determine overall survival and prognostic variables. Methods We reviewed records of pediatric patients (age <22y) with non-CNS rhabdoid tumor at our institution between 1980 and 2014. Variables evaluated for correlation with survival included: age > or <1.5 years (median) at diagnosis, M1 status, and radiation therapy. The log-rank test was used to compare Kaplan-Meier probability distributions with P values adjusted for multiple testing using the false discovery rate approach. Results Nineteen consecutive patients (10 female) with histologically verified rhabdoid tumor were identified. Mean age at diagnosis was 3.2 years (median 1.5y, range 1.3mo–21.8y). Primary tumors were located in the kidney (n=10), head and neck (n=5), and in the liver, thigh, mediastinum and retroperitoneum (n=1 each). SMARCB1 expression was absent in all 10 patients tested. Eight patients had distant metastases at diagnosis. Median overall survival was 1.2 years. Age greater than the median and radiation therapy were associated with better outcome, with a median overall survival of 2.7 years (P=0.049 and P=0.003, respectively). Conclusion Survival rates for rhabdoid tumor remain poor, but prognosis is better in older children, regardless of primary tumor location. Because of its rarity, clinical trials with present agents are difficult to conduct. Further progress will require a focus on therapies targeted at tumor biology rather than anatomic location for non-CNS rhabdoid tumors.

Purpose To evaluate factors associated with progression-free and disease-specific survival in patients with paratesticular rhabdomyosarcoma, we performed a cohort study. Also, since many patients present to our institution after initial therapy, we analyzed the effects of salvage therapy for scrotal violation. Patients and Methods We retrospectively reviewed the records of all consecutive patients with histologically confirmed paratesticular rhabdomyosarcoma treated at our institution between 1978 and 2015. Fifty-one patients were initially identified, but two were excluded due to incomplete data for analysis. Variables evaluated for correlation with survival were TNM staging, COG-STS pretreatment staging, margins at initial resection, presence of scrotal violation, hemiscrotectomy and/or scrotal radiation. The log-rank test was used to compare survival distributions. Results For the analytic cohort of 49 patients, the median age and follow-up were 15.7 years (95% CI: 14.2-17.5, range: 0.8-25.1 years) and 6.9 years (95% CI: 4.4-9.0, range 0.2-37.5 years), respectively. The 5-year overall disease-specific survival was 78.7% (95% CI: 67.7-91.4%) and the progression-free survival was 66.9% (95% CI: 54.8-81.6%). Median time to recurrence was 0.9 years (95% CI: 0.7-0.9, range 0.1-6.2 years). Scrotal violation occurred in 41% (n=20) and tripled the risk of recurrence for patients not appropriately treated with either hemiscrotectomy or scrotal radiation therapy (RR=3.0, 95% CI: 1.16-7.73). Conclusions The strongest predictors of disease-specific survival were nodal status and distant metastasis at diagnosis. Scrotal violation remains a problem in paratesticular rhabdomyosarcoma and is a predictor of disease progression unless adequately treated. The risk of progression could be reduced with appropriate initial resection.

Background Although nephrectomy rates are higher in children with neuroblastoma who have image-defined risk factors and/or high-risk disease who undergo resection prior to chemotherapy, no published data outline the key radiographic and clinical characteristics associated with nephrectomy. Methods With IRB approval, imaging studies of children undergoing primary resection of intra-abdominal neuroblastoma between 2000 and 2014 were retrospectively reviewed. Fisher’s exact and Wilcoxon rank-sum tests were used to compare categorical and continuous variables, respectively, with p-values adjusted for multiple testing using the false discovery rate approach. Results Twenty-seven of 380 consecutive patients with CT imaging obtained prior to primary neuroblastoma resection underwent partial or total nephrectomy. On preoperative imaging, renal vessel narrowing and encasement and tumor invasion of the renal hilum, pelvis, and/or parenchyma were present significantly more frequently among patients undergoing nephrectomy. Delayed renal excretion of contrast, hydronephrosis, and tumors with MYCN amplification were also more prevalent in the nephrectomy group. Conclusion Encasement and narrowing of renal vessels, delayed excretion, and tumor invasion into the kidney, particularly pelvis and capsule invasion, are significantly associated with partial or total nephrectomy at initial neuroblastoma resection. These observations provide valuable information for surgical planning as well as presurgical discussions with families prior to neuroblastoma resection.

Purpose Treatment of progression in high-risk neuroblastoma remains challenging despite improved survival. We retrospectively evaluated outcomes in children with a first progression that included soft-tissue masses. Methods We reviewed records of 903 consecutive children with high-risk neuroblastoma diagnosed between 2004 and 2014, and identified 42 whose first progression included soft-tissue masses. Data on demographics, disease characteristics, treatment, and survival were collected. Primary outcome was 5-year overall survival (OS) from time of first progression. Secondary outcomes were local disease-free progression (LDFR) and progression-free survival (PFS) post-progression. We evaluated the prognostic significance of concomitant bone/bone marrow involvement, MYCN status, and multifocality of soft tissue relapse. Data are given as median(range). Results Median age at diagnosis was 3.0 (1 – 10.7) years. Median time to first relapse or progression was 1.2 (0.1 – 4.5) years after complete remission or minimal stable residual disease Twelve (29%) patients had concomitant bone or marrow involvement at progression/relapse. There were 11 (26%) patients with INSS stage 3 disease (all with MYCN amplification), and 31 (74%) with stage 4 disease (12 with MYCN amplification). Nine (21%) patients had multifocal soft tissue progression. R1 resection was achieved in 41 children (95%), 38 (95%) of whom also received salvage radiation therapy. Five-year OS post-progression was 35% (95%CI: 19–51%), 5-year LDFS was 52% (95%CI: 32–72%), and 5-year PFS post-progression was 20% (95%CI: 6–34%). Conclusion Among children with high-risk neuroblastoma who underwent aggressive treatment of a first soft-tissue recurrence, 5-year post-progression overall survival was 34%. Multifocality and MYCN amplification were the predominant prognostic correlates for worse survival.