Transcriptomic characterization of fibrolamellar hepatocellular carcinoma.

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.

Unilateral Complete Agenesis of Mesonephric Duct Derivatives in an 82-year-Old Male Cadaver: Embryology, Anatomy and Clinical Considerations.

Development of urogenital anatomy in the human fetus is the result of a complex interplay between multiple different tissues. The time course of development is well documented and the morphologic outcomes of insults at various time points during development are predictable. We present a cadaveric case of unilateral agenesis of the left kidney, ureter, bladder hemitrigone, ureteric opening, seminal vesicle, vas deferens, and epididymis. Failure of development of the mesonephric duct early during embryogenesis, likely between the third and fifth week, caused ipsilateral urogenital organ agenesis.

Portomesenteric Vein Thrombosis, Bowel Gangrene, and Bilateral Pulmonary Artery Embolism Two Weeks after Laparoscopic Sleeve Gastrectomy.

Sleeve gastrectomy and gastric bypass surgery are popular and effective options for weight loss surgery. Portomesenteric vein thrombosis (PMVT) is a documented but rare complication of bariatric surgery. Proper surgical technique, careful postoperative prophylaxis, and early mobilization are essential to prevent this event. The diagnosis of PMVT in the postoperative period requires a high index of suspicion and early directed intervention to prevent a possibly fatal outcome. We present a case of PMVT complicated by small bowel ischemia resulting in gangrene that necessitated resection.

The genomic landscape of fibrolamellar hepatocellular carcinoma: whole genome sequencing of ten patients.

Fibrolamellar hepatocellular carcinoma is a rare, malignant liver tumor that often arises in the otherwise normal liver of adolescents and young adults. Previous studies have focused on biomarkers and comparisons to traditional hepatocellular carcinoma, and have yielded little data on the underlying pathophysiology. We performed whole genome sequencing on paired tumor and normal samples from 10 patients to identify recurrent mutations and structural variations that could predispose to oncogenesis. There are relatively few coding, somatic mutations in this cancer, putting it on the low end of the mutational spectrum. Aside from a previously described heterozygous deletion on chromosome 19 that encodes for a functional, chimeric protein, there were no other recurrent structural variations that contribute to the tumor genotype. The lack of a second-hit mutation in the genomic landscape of fibrolamellar hepatocellular carcinoma makes the DNAJB1-PRKACA fusion protein the best target for diagnostic and therapeutic advancements. The mutations, altered pathways and structural variants that characterized fibrolamellar hepatocellular carcinoma were distinct from those in hepatocellular carcinoma, further defining it as a distinct carcinoma.

Prognostic factors in fibrolamellar hepatocellular carcinoma in young people.

BACKGROUND/PURPOSE: Fibrolamellar hepatocellular carcinoma (FL-HCC) arises in pediatric/adolescent patients without cirrhosis. We retrospectively evaluated the impact of resection, nodal status, metastasis, and PRETEXT stage on overall survival (OS). METHODS: With IRB approval, we reviewed records of 25 consecutive pediatric patients with FL-HCC treated at our institution from 1981 to 2011. We evaluated associations between OS and PRETEXT stage, nodal involvement, metastasis, and complete resection. RESULTS: Median age at diagnosis was 17.1years (range, 11.6-20.5). Median follow-up was 2.74years (range, 5-9.5). Five (28%) patients had PRETEXT stage 1 disease, 10 (56%) had stage 2, 2 (11%) had stage 3, and 2 (11%) had stage 4 disease. On presentation, 17 (68%) patients had N1 disease, and 7 (28%) had parenchymal metastases. Complete resection was achieved in 17 (80.9%) of 21 patients who underwent resection. Five-year OS was 42.6%. Survival was positively associated with complete resection (P =0.003), negative regional lymph nodes (P =0.044), and lower PRETEXT stage (P <0.001), with a trend for metastatic disease (P =0.05). CONCLUSIONS: In young patients with FL-HCC, lower PRETEXT stage and complete resection correlated with prolonged survival, while metastatic disease and positive lymph node status were associated with poor prognosis. Thus, we recommend complete resection and regional lymphadenectomy whenever possible.

"Trap-door" and "clamshell" surgical approaches for the management of pediatric tumors of the cervicothoracic junction and mediastinum.

BACKGROUND/PURPOSE: For pediatric tumors of the cervicothoracic junction, an isolated cervical or thoracic surgical approach provides insufficient exposure for achieving complete resection. We retrospectively examined "trap-door" and "clamshell" pediatric thoracotomies as a surgical approach to these tumors. METHODS: We searched our database for pediatric patients with cervicothoracic tumors who underwent clamshell or trap-door thoracotomy between 1991 and 2013, reviewing tumor characteristics, surgical technique, completeness of resection, morbidity, and outcome. RESULTS: Trap-door (n=13) and clamshell (n=4) thoracotomies were performed for neuroblastoma (n=9), non-rhabdomyosarcoma soft tissue sarcoma (n=4), germ cell tumor (n=2), rhabdomyosarcoma (n=1), and neuroendocrine small cell carcinoma (n=1). Fourteen of these cervicothoracic tumors were primary, and three were metastatic. Gross total resection was achieved in 15 patients (94%). Operative complications included vocal cord paralysis (n=2), mild upper-extremity neuropraxia (n=2), and hemidiaphragm paralysis (n=1), All but one involved encased nerves. Overall survival was 61% for the series and 80% for patients with primary tumors. Eleven (73%) of 15 patients who underwent gross total resection had no evidence of recurrence. Three patients with metastatic disease died of distant progression within 1.3years. CONCLUSIONS: Gross total resection of primary cervicothoracic tumors can be accomplished with specialized exposure in pediatric patients with minimal morbidity.

Endogenous antibodies for tumor detection.

The study of cancer immunology has provided diagnostic and therapeutic instruments through serum autoantibody biomarkers and exogenous monoclonal antibodies. While some endogenous antibodies are found within or surrounding transformed tissue, the extent to which this exists has not been entirely characterized. We find that in transgenic and xenograft mouse models of cancer, endogenous gamma immunoglobulin (IgG) is present at higher concentration in malignantly transformed organs compared to non-transformed organs in the same mouse or organs of cognate wild-type mice. The enrichment of endogenous antibodies within the malignant tissue provides a potential means of identifying and tracking malignant cells in vivo as they mutate and diversify. Exploiting these antibodies for diagnostic and therapeutic purposes is possible through the use of agents that bind endogenous antibodies.

Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis. We identified a chimeric transcript that is expressed in FL-HCC but not in adjacent normal liver and that arises as the result of a ~400-kilobase deletion on chromosome 19. The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity. Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the FL-HCCs examined (15/15) suggests that this genetic alteration contributes to tumor pathogenesis.