Carcinosarcoma with chondroid differentiation and neuroendocrine carcinoma: unusual triphasic tumour arising from intracholecystic papillary neoplasm of the gall bladder.

Herein, we report a man in his 70s with gallbladder mass. Microscopically, the tumour demonstrated moderately differentiated adenocarcinoma, sarcoma with focal chondroid differentiation and high-grade neuroendocrine tumour component arising in an intracholecystic papillary neoplasm. The patient did not receive adjuvant chemotherapy in the setting of complete surgical resection. Patient presented with extensive metastasis after 47 months and died 3 months later. Due to the low incidence and poor prognosis of this tumour, it is essential to gather all the individual experience-based information. To our knowledge, this is the first reported case of carcinosarcoma arising from intracholecystic papillary-tubular neoplasm.

Multi-Center Follow-up Study to Develop a Classification System Which Differentiates Mucinous Cystic Neoplasm of the Liver and Benign Hepatic Cyst Using Machine Learning.

RATIONALE AND OBJECTIVES: To date, no clinically useful classification system has been developed for reliably differentiating mucinous cystic neoplasm (MCN) from a benign hepatic cyst (BHC) in the liver. The objective was to use machine learning and a multi-center study design to develop and assess the performance of a novel classification system for predicting whether a hepatic cystic lesion represents MCN or BHC. MATERIALS AND METHODS: A multi-center cohort study identified 154 surgically resected hepatic cystic lesions in 154 subjects which were pathologic confirmed as MCN (43) or BHC (111). Readers at each institution recorded seven pre-determined imaging features previously identified as potential differentiating features from prior publications. The contribution of each of these features to differentiating MCN from BHC was assessed by machine learning to develop an optimal classification system. RESULTS: Although several of the assessed imaging features demonstrated statistical significance, only 3 imaging features were found by machine learning to significantly contribute to a potential classification system: (1) solid enhancing nodule (2) all septations arising from an external macro-lobulation (3) whether the lesion was solitary or one of multiple cystic liver lesions. The optimal classification system had only four categories and correctly identified 144/154 lesion (93.5%). CONCLUSION: This multi-center follow-up study was able to use machine learning to develop a highly accurate classification system for differentiation of hepatic MCN from BHC, which could be readily applied to clinical practice.

The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor.

Aggressive therapies for patients with metastatic Wilms tumor (WT) with subsequent severe late effects warrant the search for novel therapies. The role of focal adhesion kinase (FAK), a non-receptor tyrosine kinase important in pediatric solid tumor development and progression, has not been examined in metastatic WT. Using a novel patient-derived xenograft (PDX) of a primary and matched, isogenic, metastatic WT, the hypothesis of the current study was that FAK would contribute to metastatic WT and small molecule inhibition would decrease tumor growth. Immunohistochemical staining, immunoblotting, cell viability and proliferation assays, cell cycle analysis, and cellular motility and attachment-independent growth assays were performed. FAK was present and phosphorylated in both WT PDXs and in the human samples from which they were derived. FAK inhibition decreased cellular survival, proliferation, and cell cycle progression in both PDXs but only significantly decreased migration, invasion, and attachment-independent growth in the primary WT PDX. Kinomic profiling revealed that platelet-derived growth factor receptor beta (PDGFRß) may be affected by FAK inhibition in WT. Pharmacologic inhibition of FAK and PDGFRß was synergistic in primary WT PDX cells. These findings broaden the knowledge of metastatic WT and support further investigations on the potential use of FAK and PDGFRß inhibitors.

Synchronous and metachronous bilateral breast cancer: clinicopathologic characteristics and prognostic outcomes.

The incidence of bilateral breast cancer (BBC) reportedly ranges from 1.4 to 11.8%. Women with a first primary breast cancer are at a 2- to 6-fold increased risk of developing contralateral BC. However, there have been limited studies analyzing the clinicopathologic features of BBC and conflicting data exist on the prognostic significance of BBC. In this study, we sought to analyze the incidence of BBC in the era of modern medicine and assess the clinicopathologic characteristics and prognostic outcomes compared to unilateral BC (UBC). Of the 5941 patients with stage I-III BC diagnosed between 1998 and 2013 at our institution, 110 developed BBC, including 58 synchronous BBC (SBBC, interval between the first and the contralateral BC ≤3 months) and 52 metachronous BBC (MBBC, interval >3 months). The median time to the second tumor was 67.9 months among patients with MBBC. BBC was associated with a significantly lower rate of having a ductal type, high grade, HER2-positive or node-positive disease when compared to UBC, while no difference was found for age, race, ER/PR status, or pathologic tumor stage. When compared to MBBC, SBBC was strongly associated with a lobular phenotype, non-high grade, and ER/PR-positive disease; and further demonstrated a significantly higher concordant rate for ER, PR, and HER2 status. Patients with BBC had a significantly worse distant relapse-free survival (RFS) but a similar disease-specific survival (DSS) when compared to those with UBC. Being African American, having a high histologic grade and higher pathologic tumor or node stage was significantly associated with a worse prognosis, while SBBC was associated with a favorable RFS by multivariate analysis. Nodal status was the only independent prognosticator for DSS in patients with BBC. Further investigation into the complex biologic and clinical behavior of BBC may provide novel insights into the therapeutic strategies in the pursuit of precision medicine in this unique subset of patients.

Targeting PIM kinase as a therapeutic strategy in human hepatoblastoma.

Increasing incidence coupled with poor prognosis and treatments that are virtually unchanged over the past 20 years have made the need for the development of novel therapeutics for hepatoblastoma imperative. PIM kinases have been implicated as drivers of tumorigenesis in multiple cancers, including hepatocellular carcinoma. We hypothesized that PIM kinases, specifically PIM3, would play a role in hepatoblastoma tumorigenesis and that PIM kinase inhibition would affect hepatoblastoma in vitro and in vivo. Parameters including cell survival, proliferation, motility, and apoptosis were assessed in human hepatoblastoma cells following PIM3 knockdown with siRNA or treatment with the PIM inhibitor AZD1208. An in vivo model of human hepatoblastoma was utilized to study the effects of PIM inhibition alone and in combination with cisplatin. PIM kinases were found to be present in the human hepatoblastoma cell line, HuH6, and in a human hepatoblastoma patient-derived xenograft, COA67. PIM3 knockdown or inhibition with AZD1208 decreased cell survival, attachment independent growth, and motility. Additionally, inhibition of tumor growth was observed in a hepatoblastoma xenograft model in mice treated with AZD1208. Combination therapy with AZD1208 and cisplatin resulted in a significant increase in animal survival when compared to either treatment alone. The current studies showed that PIM kinase inhibition decreased human hepatoblastoma tumorigenicity both in vitro and in vivo, implying that PIM inhibitors may be useful as a novel therapeutic for children with hepatoblastoma.

Effect of Repeat Dosing of Engineered Oncolytic Herpes Simplex Virus on Preclinical Models of Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS), a tumor of skeletal muscle origin, is the most common sarcoma of childhood. Despite multidrug chemotherapy regimens, surgical intervention, and radiation treatment, outcomes remain poor, especially in advanced disease, and novel therapies are needed for the treatment of these aggressive malignancies. Genetically engineered oncolytic viruses, such as herpes simplex virus-1 (HSV), are currently being explored as treatments for pediatric tumors. M002, an oncolytic HSV, has both copies of the γ134.5 gene deleted, enabling replication in tumor cells but thwarting infection of normal, postmitotic cells. We hypothesized that M002 would infect human RMS tumor cells and lead to decreased tumor cell survival in vitro and impede tumor growth in vivo. In the current study, we demonstrated that M002 could infect, replicate in, and decrease cell survival in both embryonal (ERMS) and alveolar rhabdomyosarcoma (ARMS) cells. Additionally, M002 reduced xenograft tumor growth and increased animal survival in both ARMS and ERMS. Most importantly, we showed for the first time that repeated dosing of oncolytic virus coupled with low-dose radiation provided improved tumor response in RMS. These findings provide support for the clinical investigation of oncolytic HSV in pediatric RMS.

Targeting Focal Adhesion Kinase Suppresses the Malignant Phenotype in Rhabdomyosarcoma Cells.

Despite the tremendous advances in the treatment of childhood solid tumors, rhabdomyosarcoma (RMS) continues to provide a therapeutic challenge. Children with metastatic or relapsed disease have a disease-free survival rate under 30%. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumorigenesis. Signaling pathways both upstream and downstream to FAK have been found to be important in sarcoma tumorigenesis, leading us to hypothesize that FAK would be present in RMS and would impact cellular survival. In the current study, we showed that FAK was present and phosphorylated in pediatric alveolar and embryonal RMS tumor specimens and cell lines. We also examined the effects of FAK inhibition upon two RMS cell lines utilizing parallel approaches including RNAi and small molecule inhibitors. FAK inhibition resulted in decreased cellular survival, invasion, and migration and increased apoptosis. Furthermore, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse RMS xenograft model. The findings from this study will help to further our understanding of the regulation of tumorigenesis in RMS and may provide desperately needed novel therapeutic strategies for these difficult-to-treat tumors.