Human liver organoids for disease modeling of fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a rare, often lethal, liver cancer affecting adolescents and young adults, for which there are no approved therapeutics. The development of therapeutics is hampered by a lack of in vitro models. Organoids have shown utility as a model system for studying many diseases. In this study, tumor tissue and the adjacent non-tumor liver were obtained at the time of surgery. The tissue was dissociated and grown as organoids. We developed 21 patient-derived organoid lines: 12 from metastases, three from the liver tumor and six from adjacent non-tumor liver. These patient-derived FLC organoids recapitulate the histologic morphology, immunohistochemistry, and transcriptome of the patient tumor. Patient-derived FLC organoids were used in a preliminary high-throughput drug screen to show proof of concept for the identification of therapeutics. This model system has the potential to improve our understanding of this rare cancer and holds significant promise for drug testing and development.

The Successful Implementation of a Laparoscopic Simulation Training Program in the Dominican Republic.

INTRODUCTION: Mount Sinai Hospital in New York introduced a laparoscopic surgery simulation center to a public hospital in Santiago, Dominican Republic to determine the feasibility of training programs in low-and-middle income countries (LMICs). METHODS: In August 2018, recruitment and preliminary data were collected at the Hospital Jose Maria Cabral y Báez in Santiago, Dominican Republic. The simulation room consists of three simulation stations. Residents were required to practice 1 h/wk guided by a general surgery postgraduate year 3 (PGY3) Mount Sinai resident. Number of hours practiced was self-reported and follow-up data was collected in June 2019. The study endpoints include times on three simulated laparoscopic tasks including peg-transfer, precision cutting, and intracorporeal knot tying. Wilcoxon-signed rank tests were used for statistical analysis. RESULTS: The partnership between hospitals allowed for successful integration into the Dominican general surgery training. Over 10 mo, residents averaged 25 h of practice (range: 8-35 h; SD 9.95 h). In total, 85% of the residents participated in the study (5 postgraduate year 1 [PGY1], 2 postgraduate year 2 [PGY2], and 4 postgraduate year 3 [PGY3]). Resident median simulation times significantly improved for precision cutting (3:49 min versus 2:09 min, P = 0.002) and intracorporeal knot tying (5:20 min versus 2:47 min, P = 0.037). There was neither significant difference in peg-transfer times nor performance between resident years (P = 0.12). CONCLUSIONS: This study demonstrates the successful integration of a laparoscopic simulation program into an LMIC surgical resident training program. With commitment from local institutions and external resources, establishing laparoscopic simulation centers are feasible and expandable, thereby allowing general surgery residents in other LMICs, the opportunity to improve their laparoscopic skills.

Identification of Novel Therapeutic Targets for Fibrolamellar Carcinoma Using Patient-Derived Xenografts and Direct-from-Patient Screening.

To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. SIGNIFICANCE: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor.This article is highlighted in the In This Issue feature, p. 2355.

Survival and Scoliosis Following Resection of Chest Wall Tumors in Children and Adolescents: A Single-center Retrospective Analysis.

OBJECTIVE: We reviewed our experience with pediatric chest wall tumors (CWTs) to identify variables associated with survival, scoliosis development, and need for corrective scoliosis surgery. BACKGROUND: Chest wall neoplasms in children or adolescents are rare. Consequently, there are few large series that detail survival or quality of life indicators, like scoliosis. METHODS: Medical records were reviewed for all chest wall resections for primary and metastatic CWT performed from October 1, 1986 to September 30, 2016 on patients 21 years or younger at diagnosis. Kaplan-Meier distributions were compared using the log-rank test. Variables correlated with survival, scoliosis development, or need for corrective surgeries were analyzed using competing-risk analysis. RESULTS: Seventy-six cases [57 (75%) primary, 19 (25%) metastatic] were identified. Median age at diagnosis was 15.6 years (range: 0.5-21 years). Tumor types were Ewing sarcoma family tumors (54%), other soft tissue sarcomas (21%), osteosarcoma (11%), rhabdomyosarcoma (7%), and other (8%). A median of 3 (range: 1-5) contiguous ribs were resected. Surgical reconstruction included composite Marlex mesh and methyl-methacrylate, Gore-Tex, or primary closure in 57%, 28%, and 14% of procedures, respectively. Overall 5-year survival was 61% (95% confidence interval: 50%-75%). Scoliosis developed in 19 (25%) patients; 6 patients required corrective surgery. Variables associated with overall survival were the presence of metastatic disease at diagnosis, and whether the chest tumor itself was a primary or metastatic lesion. Younger age at chest wall resection was associated with the need for corrective surgery in patients who developed scoliosis. CONCLUSIONS: Among pediatric and adolescent patients with CWTs, survival depends primarily on the presence of metastases. Age, type of chest wall reconstruction, and tumor size are not associated with scoliosis development. Among patients who develop scoliosis, younger patients are more likely to require corrective surgery.

A Human Organoid Model of Aggressive Hepatoblastoma for Disease Modeling and Drug Testing.

Hepatoblastoma is the most common childhood liver cancer. Although survival has improved significantly over the past few decades, there remains a group of children with aggressive disease who do not respond to current treatment regimens. There is a critical need for novel models to study aggressive hepatoblastoma as research to find new treatments is hampered by the small number of laboratory models of the disease. Organoids have emerged as robust models for many diseases, including cancer. We have generated and characterized a novel organoid model of aggressive hepatoblastoma directly from freshly resected patient tumors as a proof of concept for this approach. Hepatoblastoma tumor organoids recapitulate the key elements of patient tumors, including tumor architecture, mutational profile, gene expression patterns, and features of Wnt/ß-catenin signaling that are hallmarks of hepatoblastoma pathophysiology. Tumor organoids were successfully used alongside non-tumor liver organoids from the same patient to perform a drug screen using twelve candidate compounds. One drug, JQ1, demonstrated increased destruction of liver organoids from hepatoblastoma tumor tissue relative to organoids from the adjacent non-tumor liver. Our findings suggest that hepatoblastoma organoids could be used for a variety of applications and have the potential to improve treatment options for the subset of hepatoblastoma patients who do not respond to existing treatments.

A novel image-based system for risk stratification in patients with desmoplastic small round cell tumor.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an aggressive soft tissue sarcoma affecting children and young adults with 5-year overall survival (OS) of approximately 20%. Despite generally poor prognosis, long-term survival does occur. However, no evidence-based system exists to risk-stratify patients at diagnosis. METHODS: We retrospectively reviewed all DSRCT cases diagnosed at our institution between January 2000 and September 2016. Demographics, diagnostic imaging, and clinical data were reviewed. Univariate and multivariate Cox proportional hazard modeling was used to evaluate associations between imaging characteristics and OS. RESULTS: There were 130 patients (85% male; median age at presentation: 21.2 years) with confirmed DSRCT and sufficient imaging and clinical information for analysis. Median 5-year OS was 28% (95% CI: 19%-37%). In univariate analysis, shorter OS was associated with presence of liver lesions (hazard ratio [HR] 2.1, 95% CI: 1.28-3.45), chest lesions (HR 1.86, 95% CI: 1.11-3.1), and ascites (HR 1.69, 95% CI: 1.06-2.7). In multivariate analysis, liver involvement and ascites were predictive and were used to stratify risk (intermediate=no liver involvement or ascites; high=either liver involvement or ascites; very high=both liver involvement and ascites). Intermediate-risk patients had a 5-year survival of 61% (95% CI: 40%-76%) versus 16% (95% CI: 6%-29%) among high-risk patients and 8% (95% CI: 1%-29%) among very high risk patients. CONCLUSION: Patients with DSRCT can be risk-stratified at diagnosis based on specific imaging characteristics. TYPE OF STUDY: Retrospective study with no comparison group. LEVEL OF EVIDENCE: Level IV.

Intracranial metastasis in fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy in adolescents and young adults. Surgery is the mainstay of therapy for primary and metastatic disease. Most patients relapse, with development of both local and distant metastases. Brain metastases from solid tumors are rare in the pediatric and young adult population. Here, we document three patients with brain metastases from FLHCC, confirmed by histology and molecular characterization of the chimeric fusion DNAJB1-PRKACA, each necessitating neurosurgical intervention. These observations highlight the ability of FLHCC to metastasize to the brain and suggest the need for surveillance neuroimaging for patients with advanced-stage disease.

Urothelial neoplasms in pediatric and young adult patients: A large single-center series.

PURPOSE: Bladder cancer is the sixth most common cancer in the United States, but is exceedingly rare in young patients, leading to a lack of accepted standards for diagnosis, treatment, and surveillance. We review our institutional experience with bladder urothelial neoplasms in pediatric and young adult patients summarizing presentation, treatment, and outcomes. METHODS: Surgical pathology records at our institution were searched for cases of urothelial neoplasms among patients ≤25 years of age treated between January 1997 and September 2016. Cases submitted exclusively for pathology review were excluded. Diagnoses were confirmed based on pathologic examination using the 2004 World Health Organization classification system. RESULTS: Thirty-four patients were identified with a mean age of 21.1 years (range 8-25 years), and median follow-up was 25.1 months (1-187 months). The male to female ratio was 1.83:1. The most common presenting symptom was hematuria (n=26; 76%). Diagnoses were invasive urothelial carcinoma (n=3), noninvasive urothelial carcinoma (n=24), PUNLMP (n=6), and urothelial papilloma (n=1). Noninvasive lesions were resected by cystoscopy, after which 12% (n=4) experienced complications (grade II or greater). One patient with stage IV invasive disease at diagnosis died, and 2 patients developed recurrences. Of those with noninvasive carcinoma, 29% (n=7) required repeat cystoscopy soon after initial TURBT at outside institutions, and 17% (n=4) had tumors downgraded from high-grade to low-grade after pathology review. CONCLUSION: Hematuria is the most common sign of bladder neoplasia in children and young adults and should be investigated by cystoscopy. The majority of urothelial neoplasms in these patients are noninvasive and can be successfully treated with transurethral resection. LEVEL OF EVIDENCE: Level IV (Retrospective study with no comparison group).

Rapid progression of carotid artery atherosclerosis and stenosis in a patient with a ventricular assist device.

This case describes the management of cerebrovascular disease in a patient with a left ventricular assist device (LVAD) who was awaiting cardiac transplantation. It demonstrates several unique features in managing vascular disease in patients with cardiac assist devices. First, we detail the difficulties in using duplex ultrasound to assess patients with altered hemodynamic physiology. Second, we report an instance of rapid progression of known carotid stenosis in a patient with a recently placed LVAD. This case suggests that patients with any degree of carotid stenosis before LVAD placement should be monitored closely for progression after the LVAD is placed.