Goblet Cell Tumors of the Appendix: Clinical & Molecular Features

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Utility of plasma tumor marker levels in management of patients with appendiceal adenocarcinoma

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Understanding the Value of Tumor Markers in Pediatric Ovarian Neoplasms

Purpose The purpose of this study was to determine the diagnostic accuracy of tumor markers for malignancy in girls with ovarian neoplasms. Methods A retrospective review of girls 2–21 years who presented for surgical management of an ovarian neoplasm across 10 children's hospitals between 2010 and 2016 was performed. Patients who had at least one concerning feature on imaging and had tumor marker testing were included in the study. Sensitivity, specificity, and negative and positive predictive values (PPV) of tumor markers were calculated. Results Our cohort included 401 patients; 22.4% had a malignancy. Testing for tumor markers was inconsistent. AFP had high specificity (98%) and low sensitivity (42%) with a PPV of 86%. The sensitivity, specificity, and PPV of beta-hCG was 44%, 76%, and 32%, respectively. LDH had high sensitivity (95%) and Inhibin A and Inhibin B had high specificity (97% and 92%, respectively). Conclusions Tumor marker testing is helpful in preoperative risk stratification of ovarian neoplasms for malignancy. Given the variety of potential tumor types, no single marker provides enough reliability, and therefore a panel of tumor marker testing is recommended if there is concern for malignancy. Prospective studies may help further elucidate the predictive value of tumor markers in a pediatric ovarian neoplasm population

Delivery strategies for the chaperonin subunit domain ApiCCT1 in Huntington’s disease

Huntington’s disease (HD) is a genetic neurodegenerative disease caused by a polyglutamine (PolyQ) repeat expansion within the Huntingtin (HTT) protein. One of the hallmarks of Huntington’s disease is aberrant accumulation and aggregation of misfolded mutant HTT (mHTT), leading to production of large inclusion bodies within cells. While the precise impact of aggregation in HD is not clear, studies suggest that smaller, soluble forms of mHTT accumulation may confer toxicity. The chaperone protein CCT (chaperonin containing TCP-1/TCP-1 ring) binds and folds proteins during de novo protein synthesis. Previous studies demonstrated that exogenous delivery of the substrate-binding apical domain of subunit 1 of CCT (ApiCCT1) is sufficient to decrease mHTT aggregation and rescue mHTT-mediated toxicity in multiple cell models of HD, making ApiCCT1 a promising therapeutic for HD. The goal of this dissertation is to evaluate delivery methods of a novel modifier of mHTT accumulation in mouse models of Huntington’s disease (HD).Here, we compare local, striatal viral delivery with global, systemic viral delivery and provide a proof of concept for mouse neural stem cells (mNSCs) as a delivery vehicle. Striatal in vivo delivery of ApiCCT1 with a secretion signal (sAiCCT1) targets multiple cell types, likely due to its ability to penetrate the cell membrane in multiple cell types. We find that viral delivery of sApiCCT1 to striatum provides robust expression and can modulate mHTT accumulation and motor phenotypes; however, the in vivo studies reported here were complicated by confounding factors. Further, systemic delivery of ApiCCT1 did not appear to ameliorate behavioral or biochemical outcomes in HD mice under the conditions tested. Data from viral studies suggests that ApiCCT1 is not sufficient to overcome disease phenotypes in the presence of additional stressors. Finally, we provide evidence suggesting the mNSCs engineered to secrete ApiCCT1 modulate mHTT accumulation after striatal transplantation, supporting the ability of ApiCCT1 to impact protein accumulation and aggregation. Data presented here provides support for mNSC-mediated delivery of sApiCCT1 as a therapeutic approach for Huntington’s disease and elicits important caveats and considerations for future study design involving viral delivery

Delivery strategies for the chaperonin subunit domain ApiCCT1 in Huntington’s disease

Huntington’s disease (HD) is a genetic neurodegenerative disease caused by a polyglutamine (PolyQ) repeat expansion within the Huntingtin (HTT) protein. One of the hallmarks of Huntington’s disease is aberrant accumulation and aggregation of misfolded mutant HTT (mHTT), leading to production of large inclusion bodies within cells. While the precise impact of aggregation in HD is not clear, studies suggest that smaller, soluble forms of mHTT accumulation may confer toxicity. The chaperone protein CCT (chaperonin containing TCP-1/TCP-1 ring) binds and folds proteins during de novo protein synthesis. Previous studies demonstrated that exogenous delivery of the substrate-binding apical domain of subunit 1 of CCT (ApiCCT1) is sufficient to decrease mHTT aggregation and rescue mHTT-mediated toxicity in multiple cell models of HD, making ApiCCT1 a promising therapeutic for HD. The goal of this dissertation is to evaluate delivery methods of a novel modifier of mHTT accumulation in mouse models of Huntington’s disease (HD).Here, we compare local, striatal viral delivery with global, systemic viral delivery and provide a proof of concept for mouse neural stem cells (mNSCs) as a delivery vehicle. Striatal in vivo delivery of ApiCCT1 with a secretion signal (sAiCCT1) targets multiple cell types, likely due to its ability to penetrate the cell membrane in multiple cell types. We find that viral delivery of sApiCCT1 to striatum provides robust expression and can modulate mHTT accumulation and motor phenotypes; however, the in vivo studies reported here were complicated by confounding factors. Further, systemic delivery of ApiCCT1 did not appear to ameliorate behavioral or biochemical outcomes in HD mice under the conditions tested. Data from viral studies suggests that ApiCCT1 is not sufficient to overcome disease phenotypes in the presence of additional stressors. Finally, we provide evidence suggesting the mNSCs engineered to secrete ApiCCT1 modulate mHTT accumulation after striatal transplantation, supporting the ability of ApiCCT1 to impact protein accumulation and aggregation. Data presented here provides support for mNSC-mediated delivery of sApiCCT1 as a therapeutic approach for Huntington’s disease and elicits important caveats and considerations for future study design involving viral delivery

Taxane-Based Chemotherapy Is Effective in Metastatic Appendiceal Adenocarcinoma.

Appendiceal cancer is a rare, orphan disease with no therapies currently approved by the FDA for its treatment. Given the limited data regarding drug efficacy, these tumors have historically been treated with chemotherapy designed for colon cancer. However, an overwhelming body of molecular data has demonstrated that appendiceal adenocarcinoma is a distinct entity with key molecular differences from colon cancer, notably rare APC mutation. Recognizing that APC loss-of-function is thought to contribute to taxane resistance and that taxanes are effective in the treatment of other gastrointestinal tumors, including gastric, esophageal, and small bowel adenocarcinoma, we completed a single-center retrospective study to assess efficacy. In a cohort of 13 patients with metastatic appendiceal adenocarcinoma, treated with taxane chemotherapy the median overall survival was 8.8 months. Of 10 evaluable patients, we observed 3 responses, 4 patients with stable disease, and 3 with progression (30% response rate, 70% disease control rate). The results of this study showing activity of taxane-based chemotherapy in appendiceal adenocarcinoma support further clinical investigation of taxane therapy in this orphan disease

Longitudinal Biochemical Assay Analysis of Mutant Huntingtin Exon 1 Protein in R6/2 Mice.

BACKGROUND: Biochemical analysis of mutant huntingtin (mHTT) aggregation species in HD mice is a common measure to track disease. A longitudinal and systematic study of how tissue processing affects detection of conformers has not yet been reported. Understanding the homeostatic flux of mHTT over time and under different processing conditions would aid in interpretation of pre-clinical assessments of disease interventions. OBJECTIVE: Provide a systematic evaluation of tissue lysis methods and molecular and biochemical assays in parallel with behavioral readouts in R6/2 mice to establish a baseline for HTT exon1 protein accumulation. METHODS: Established biochemical methods were used to process tissue from R6/2 mice of specific ages following behavior tasks. Aggregation states and accumulation of mHTT exon 1 protein were evaluated using multiple break and assay methods to determine potential conformational flux assay specificity in detection of mHTT species, and tissue specificity of conformers. RESULTS: Detection of mHTT exon 1 protein species varied based on biochemical processing and analysis providing a baseline for subsequent studies in R6/2 mice. Insoluble, high molecular weight species of mHTT exon 1 protein increased and tracked with onset of behavioral impairments in R6/2 mice using multiple assay methods. CONCLUSIONS: Conformational flux from soluble monomer to high molecular weight, insoluble species of mHTT exon 1 protein was generally consistent for multiple assay methods throughout R6/2 disease progression; however, the results support the use of multiple biochemical techniques to detect mHTT exon 1 protein species for preclinical assessments in HD mouse models expressing mHTT exon 1 protein