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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).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.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).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.

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

Supplementary Figure 1 - 6 and Supplementary Tables 1, 2, and 4

List of compounds in the primary screen

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

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.

Fibrolamellar Hepatocellular Carcinoma (FLC) is a rare liver cancer affecting adolescents and young adults, with no gender or ethnicity predilection and without history of underlying viral hepatitis, cirrhosis, or other known risk factors. Almost all FLC patients present a somatic heterozygous deletion in chromosome 19p13.12, DNAJB1::PRKACA, which is sufficient to drive FLC in mice. A few studies comparing FLC tumors with adjacent non-transformed liver (normal) samples revealed many transcriptional differences. However, there were done in very small datasets and analyzed using different bioinformatic methods, resulting in just 18-47% agreement between them. This study aims to comprehensively characterize the transcriptome of FLC at bulk and spatial single-cell resolution. The whole transcriptome of 109 FLC frozen patient samples, the largest RNA-seq dataset of FLC to date, was sequenced using different library preparation and ribosomal depletion methods. Only paired tumor and normal tissue samples resected from the same patient were used and divided into two groups: exploration (3 datasets, 67 samples) and testing (2 datasets, 17 samples). Additionally, as external validation datasets, RNA-seq samples from previously published studies were collected, including Sorenson et al. (FLC: 26, normal: 9, paired: 8), the TCGA-LIHC study (FLC: 6, normal: 1, paired: 1), Hirsch et al. (FLC: 15, normal: 3, paired: 0) and Francisco et al. (FLC: 27, normal: 10, paired: 9). All were reanalyzed using state-of-the-art bioinformatic methods: mapped to the Human Genome GRCh38.103 and transcripts quantified using Salmon 1.6.0, unsupervised clustering exploration using PCA, tSNE and UMAP, differential expression calculated using DESeq2 1.28.1, and checking for detectability and consistency among datasets. We found 857 up- and 988 down-regulated genes presenting the same dysregulation in the exploration datasets and confirmed in the testing and external datasets. We call these genes the transcriptional FLC signature. The FLC signature was further characterized by comparing it with the genes differentially expressed in other liver cancers: hepatocellular carcinoma (41 paired samples), hepatoblastoma (22 paired samples), and cholangiocarcinoma (27 paired samples). We found 276 up- and 352 down-regulated genes altered in other liver cancers as well as FLC, but 156 up- and 68 down-regulated only in FLC. The 112 genes with the strongest dysregulation (56 up and 56 down) were used for a MERFISH screening, providing for the first time a single-cell spatial transcriptomic characterization of FLC. This showed clear differential expression patterns in tumor, normal, stromal, and infiltrating immune cells, allowing the identification of how different cell types contribute to the transcriptional FLC signature. Citation Format: David Requena, Aldhair Medico, Luis F. Soto, Mahsa Shirani, James A. Saltsman, Gadi Lalazar, Michael P. LaQuaglia, Sanford M. Simon. Bulk and spatial single-cell transcriptomic characterization of fibrolamellar hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1516.

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., Stem Cell Reports, 17 (8), ISSN:2213-6711

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.

Desmoplastic small round cell tumor (DSRCT) is a relatively recently identified, rare, aggressive cancer that arises from the peritoneal lining of the abdominal cavity and predominantly affects male adolescents and young adults. DSRCT is included in the Ewing family of tumors and harbors a unique translocation between EWSR and WT1 genes. Patients characteristically present with advanced disease, including widespread involvement of the abdominal cavity and pelvis, with frequent extraperitoneal metastases involving liver, spleen, and thoracic lymph nodes. Five-year overall survival remains approximately 15 to 20% in recent series despite aggressive multimodal therapy. Neoadjuvant chemotherapy, complete resection, defined as less than 1 cm3 of residual tumor, and consolidative whole abdominopelvic radiotherapy (WAP-RT) appear to play important role in curative treatment. The rarity of DSRCT makes large randomized trials difficult and consensus statements about clinical approach impossible. However, this chapter summarizes the best available data on the pathogenesis, diagnosis, and treatment of DSRCT; highlights the major advances made in these areas; and discusses the addition of local therapy to the treatment paradigm. This review contains 3 figures, 1 table, and 51 references. Key Words: DSRCT, peritoneal malignancy, desmoplastic round cell tumor, surface malignancies of the peritoneum, desmoplastic small round cell tumor of the abdomen, surgical oncology, rare malignancies, surgical therapy of abdominal malignancies

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/&beta, 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.

Fibrolamellar Hepatocellular Carcinoma (FLC) is a usually lethal liver cancer affecting adolescents and young adults without previous liver disease. FLC is characterized by a ~400kb nucleotide deletion resulting in a fusion of a heatshock protein cofactor, DNAJB1, with the catalytic subunit of protein kinase A (PRKACA). One limitation to the study of this disease is the lack of in vitro models. Organoids have shown utility as a model system for studying many diseases, including cancer. This study describes the development and characterization of FLC tumor organoids. With IRB approval, normal liver and FLC tumor tissue was obtained from patients undergoing surgical resection. Liver cells were isolated from the tissue samples and placed into a 3D basement membrane matrix and the media supplemented with growth factors specific to promote liver organoid expansion. Normal and tumor organoids were analyzed by microscopy for morphology, by PCR for presence of the DNAJB1-PRKACA chimeric transcript, by Western blot for chimeric protein expression, and by RNA sequencing for transcriptomic changes. Eight organoid lines have been developed from normal liver and eight from FLC tumor tissue, including multiple independent organoids developed from different metastases from the same patient. A distinct morphological difference between normal liver organoids and FLC tumor organoids can be seen with either brightfield microscopy or with H&E. The DNAJB1-PRKACA chimeric transcript was detected in all of the tumor tissue and tumor organoids by RT-PCR and not detected in any of the normal tissue or organoids. The presence of the DNAJB1-PRKACA fusion protein was verified by Western blot in tumor organoids and tissue but not detectable in the normal tissue. The RNA sequencing analysis shows clustering of tumor organoids with tumor tissue. Tumor organoids injected subcutaneously in mice grew as tumors. Now that the normal and tumor organoids have been developed and validated, they are being used for screening for potential therapeutics. Citation Format: Nicole J. Croteau, David Requena, Gadi Lalazar, Denise Ng, Solomon Levin, Bassem Shebl, Ruisi Wang, William J. Hammond, James A. Saltsman, Helmuth Gehart, Hans Clevers, Michael P. LaQuaglia, Sanford Simon. Human liver organoids for disease modeling of fibrolamellar hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3905.

The management of neuroblastoma requires a multidisciplinary approach led by the pediatric surgeon. Surgical biopsy and resection are essential to characterize the tumor, stratify patient risk, and guide the oncologic treatment and supportive procedures. This chapter will describe the role of surgical intervention in the management of neuroblastoma and recent advances in the field.

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.

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).

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.

The results of the application of a newly proposed thermomechanical fatigue (TMF) life prediction method to a series of laboratory TMF results on two high-temperature aerospace engine alloys are presented. The method, referred to as TMF/TS-SRP, is based on three relatively recent developments: the total strain version of the method of Strainrange Partitioning (TS-SRP), the bithermal testing technique for characterizing TMF behavior, and advanced viscoplastic constitutive models. The high-temperature data reported in a companion publication are used to evaluate the constants in the model and to provide the TMF verification data to check its accuracy. Predicted lives are in agreement with the experimental lives to within a factor of approximately 2.