Anthropometric measurements of children with neurofibromatosis type I: impact of plexiform neurofibroma volume and treatment.

BACKGROUND: In children and adolescents/young adults (CAYA) with neurofibromatosis type I (NF1), associations between anthropometric measurements, plexiform neurofibroma (pNF) tumor volume (TV), and treatment history are unknown. METHODS: We retrospectively investigated anthropometrics in CAYA on the National Cancer Institute (NCI) NF1 Natural History Study who had pNF TV assessed by imaging (n = 106). We determined CDC height/weight percentiles and estimated Preece-Baines (PB) height growth curve parameters. We evaluated variables that could impact height/weight including: (1) pNF volume, (2) pNF directed therapy, and (3) serum IGF-1. RESULTS: 23% of males and 20% of females had height <5th percentile; 13% of males had weight <5th percentile. Estimated median final adult height for males was 171.6 cm (CDC 23rd percentile) and for females was 156.2 cm (CDC 14th percentile). Inverse associations between height and weight percentiles and pNF volume were observed (Spearman's r = -0.277, -0.216, respectively). Estimated median final height was not meaningfully affected by patients who received pNF-directed treatment with MEK inhibitor. 52% of low serum IGF-1 measurements were concurrent with a height percentile <5th. CONCLUSIONS: Greater than expected percentages of patients had height/weight <5th percentile, and median final adult heights were

The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models.

PURPOSE: PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS. Our previous studies revealed preclinical efficacy of the MEK1/2 inhibitor, trametinib, and an IGF1R inhibitor, BMS-754807, but this combination was not pursued clinically due to intolerability in preclinical murine models. Here, we sought to identify a combination of an MEK1/2 inhibitor and IGF1R inhibitor, which would be tolerated in murine models and effective in both cell line and patient-derived xenograft models of RAS-mutant FN RMS. EXPERIMENTAL DESIGN: Using proliferation and apoptosis assays, we studied the factorial effects of trametinib and ganitumab (AMG 479), a mAb with specificity for human and murine IGF1R, in a panel of RAS-mutant FN RMS cell lines. The molecular mechanism of the observed synergy was determined using conventional and capillary immunoassays. The efficacy and tolerability of trametinib/ganitumab was assessed using a panel of RAS-mutated cell-line and patient-derived RMS xenograft models. RESULTS: Treatment with trametinib and ganitumab resulted in synergistic cellular growth inhibition in all cell lines tested and inhibition of tumor growth in four of six models of RAS-mutant RMS. The combination had little effect on body weight and did not produce thrombocytopenia, neutropenia, or hyperinsulinemia in tumor-bearing SCID beige mice. Mechanistically, ganitumab treatment prevented the phosphorylation of AKT induced by MEK inhibition alone. Therapeutic response to the combination was observed in models without a mutation in the PI3K/PTEN axis. CONCLUSIONS: We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models. Our data also show that the trametinib/ganitumab combination likely has a favorable tolerability profile. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated FN RMS.

Tumor Doubling Time Using CT Volumetric Segmentation in Metastatic Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy with an overall unfavorable prognosis. Clinicians treating patients with ACC have noted accelerated growth in metastatic liver lesions that requires rapid intervention compared to other metastatic locations. This study measured and compared the growth rates of metastatic ACC lesions in the lungs, liver, and lymph nodes using volumetric segmentation. A total of 12 patients with metastatic ACC (six male; six female) were selected based on their medical history. Computer tomography (CT) exams were retrospectively reviewed and a sampling of ≤5 metastatic lesions per organ were selected for evaluation. Lesions in the liver, lung, and lymph nodes were measured and evaluated by volumetric segmentation. Statistical analyses were performed to compare the volumetric growth rates of the lesions in each organ system. In this cohort, 5/12 had liver lesions, 7/12 had lung lesions, and 5/12 had lymph node lesions. A total of 92 lesions were evaluated and segmented for lesion volumetry. The volume doubling time per organ system was 27 days in the liver, 90 days in the lungs, and 95 days in the lymph nodes. In this series of 12 patients with metastatic ACC, liver lesions showed a faster growth rate than lung or lymph node lesions.

Pediatric PK/PD Phase I Trial of Pexidartinib in Relapsed and Refractory Leukemias and Solid Tumors Including Neurofibromatosis Type I-Related Plexiform Neurofibromas.

PURPOSE: Simultaneously targeting the tumor and tumor microenvironment may hold promise in treating children with refractory solid tumors. Pexidartinib, an oral inhibitor of tyrosine kinases including colony stimulating factor 1 receptor (CSF-1R), KIT, and FLT3, is FDA approved in adults with tenosynovial giant cell tumor. A phase I trial was conducted in pediatric and young adult patients with refractory leukemias or solid tumors including neurofibromatosis type 1-related plexiform neurofibromas. PATIENTS AND METHODS: A rolling six design with dose levels (DL) of 400 mg/m2, 600 mg/m2, and 800 mg/m2 once daily for 28-day cycles (C) was used. Response was assessed at regular intervals. Pharmacokinetics and population pharmacokinetics were analyzed during C1. RESULTS: Twelve patients (4 per DL, 9 evaluable) enrolled on the dose-escalation phase and 4 patients enrolled in the expansion cohort: median (lower, upper quartile) age 16 (14, 16.5) years. No dose-limiting toxicities were observed. Pharmacokinetics appeared linear over three DLs. Pharmacokinetic modeling and simulation determined a weight-based recommended phase II dose (RP2D). Two patients had stable disease and 1 patient with peritoneal mesothelioma (C49+) had a sustained partial response (67% RECIST reduction). Pharmacodynamic markers included a rise in plasma macrophage CSF (MCSF) levels and a decrease in absolute monocyte count. CONCLUSIONS: Pexidartinib in pediatric patients was well tolerated at all DL tested, achieved target inhibition, and resulted in a weight-based RPD2 dose.

Longitudinal evaluation of peripheral nerve sheath tumors in neurofibromatosis type 1: growth analysis of plexiform neurofibromas and distinct nodular lesions.

BACKGROUND: Understanding the natural history of non-malignant peripheral nerve sheath tumors (PNSTs) in neurofibromatosis type 1 (NF1) is critical to optimal clinical care and the development of meaningful clinical trials. METHODS: We longitudinally analyzed growth of plexiform neurofibromas (PNs) and of PNSTs with distinct nodular appearance (distinct nodular lesions [DNLs]) using volumetric MRI analysis in patients enrolled on a natural history study (NCT00924196). RESULTS: DNLs were observed in 58/122 (45.6%) patients (median 2 DNLs/patient). In DNLs that developed during follow-up, median age of development was 17 years. A moderate negative correlation was observed between the estimated PN growth rate and patients' age at initial MRI (Spearman's r [95% CI]: -0.60 [-0.73, -0.43], n = 70), whereas only a weak correlation was observed for DNLs (Spearman's r [95% CI]: -0.25 [-0.47, 0.004]; n = 61). We observed a moderate negative correlation between tumor growth rate and baseline tumor volume for PNs and DNLs (Spearman's r [95% CI]: -0.52 [-0.67, -0.32] and -0.61 [-0.75, -0.42], respectively). Spontaneous tumor volume reduction was observed in 10 PNs and 7 DNLs (median decrease per year, 3.6% and 7.3%, respectively). CONCLUSION: We corroborate previously described findings that most rapidly growing PNs are observed in young children. DNLs tend to develop later in life and their growth is minimally age related. Distinct growth characteristics of PNs and DNLs suggest that these lesions have a different biology and may require different clinical management and clinical trial design. In a subset of PNs and DNLs, slow spontaneous regression in tumor volume was seen.

A phase I/II study of pemetrexed with sirolimus in advanced, previously treated non-small cell lung cancer.

BACKGROUND: Single-agent pemetrexed is a treatment for recurrent non-squamous non-small cell lung cancer (NSCLC) that provides limited benefit. Preclinical studies showed promising synergistic effects when the mammalian target of rapamycin (mTOR) inhibitor sirolimus was added to pemetrexed. METHODS: This was a single-institution phase I/II study of pemetrexed in combination with sirolimus. The primary endpoint for the phase I was to determine the maximum tolerated dose (MTD) and safety of the combination. The primary endpoint for the phase II portion was to determine the overall response rate at the MTD. Key eligibility criteria included recurrent, metastatic NSCLC, ECOG performance status of 0-2, and adequate organ function. Sirolimus was administered orally daily after an initial loading dose, and pemetrexed was given intravenously on day 1 of every 21-day cycle. RESULTS: Forty-two patients with recurrent, metastatic NSCLC were enrolled, 22 in phase I and 20 in phase II. The MTD was pemetrexed 500 mg/m2 every 3 weeks, and sirolimus 10 mg on day 1, and 3 mg daily thereafter. Treatment-related adverse events (AEs) occurred in 38 (90.5%) patients. The most common grade 3-4 treatment-related AEs were lymphopenia (31%) and hypophosphatemia (19%). Two treatment-related deaths occurred due to febrile neutropenia and infection, respectively. Among 27 total patients treated at the MTD, 6 (22.2%) had a partial response (PR), 12 (44.4%) had stable disease (SD) and 5 (18.5%) had progressive disease. Median progression-free survival (PFS) was 18.4 weeks (95% CI: 7.0-29.4). CONCLUSIONS: The combination of pemetrexed and sirolimus is active in heavily-pretreated NSCLC (ClinicalTrials.gov Identifier: NCT00923273).

Differential Expression of CD43, CD81, and CD200 in Classic Versus Variant Hairy Cell Leukemia.

BACKGROUND: Hairy cell leukemia (HCL) and hairy cell leukemia variant (HCLv) are rare diseases with overlapping clinicopathological features. Features distinguishing HCL from HCLv include expression of CD25, CD123, CD200, annexin-A1, and the presence of BRAF V600E mutation. HCLv typically lacks these markers, but they may occur in a subgroup of HCL patients with an aggressive clinical course. We examined CD43, CD81, CD79b, and CD200 expression in HCL and HCLv. METHODS: Multiparametric flow cytometry (FCM) was performed on blood from 59 HCL and 15 HCLv patients for protocol entry. Mean fluorescent intensity (MFI) of CD43, CD79b, CD81, and CD200 was determined (for CD200, n = 17 and 7, respectively). RESULTS: Median MFI of HCL vs HCLv was 545 vs 272 for CD43, 602 vs 2,450 for CD81, 4,962 vs 1,969 for CD79b, and 11,652 vs 1,405 for CD200, respectively. Analysis of the median differences, HCL minus HCLv (and their 95% confidence intervals and P-values) indicated that CD43 MFI (estimated median difference (95% CI): 212 [72-413; P = 0.0027) and CD200 MFI (9,883 [3,514-13,434]; P < 0.0001) were higher in HCL than in HCLv, while CD81 MFI (-1,858 [-2,604 to -1,365]; P < 0.0001) was lower in HCL than in HCLv. CD79b MFI HCL median was more than double that of HCLv, but the observed difference (1,571 [-739 to 4,417]) was consistent with the null hypothesis of no difference (P = 0.13). CONCLUSIONS: CD200, CD43, and CD81 are likely differentially expressed between HCL and HCLv, reflecting their differing disease biology. Inclusion of these markers in FCM is potentially informative. © 2019 International Clinical Cytometry Society.

Reproducibility of pharmacogenetics findings for paclitaxel in a heterogeneous population of patients with lung cancer.

Pharmacogenetics studies have identified several allelic variants with the potential to reduce toxicity and improve treatment outcome. The present study was designed to determine if such findings are reproducible in a heterogenous population of patients with lung cancer undergoing therapy with paclitaxel. We designed a prospective multi-institutional study that recruited n = 103 patients receiving paclitaxel therapy with a 5-year follow up. All patients were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) platform, which ascertains 1931 genotypes in 235 genes. Progression-free survival (PFS) of paclitaxel therapy and clinically-significant paclitaxel toxicities were classified and compared according to genotype. Initial screening revealed eleven variants that are associated with PFS. Of these, seven variants in ABCB11 (rs4148768), ABCC3 (rs1051640), ABCG1 (rs1541290), CYP8B1 (rs735320), NR3C1 (rs6169), FMO6P (rs7889839), and GSTM3 (rs7483) were associated with paclitaxel PFS in a multivariate analysis accounting for clinical covariates. Multivariate analysis revealed four SNPs in VKORC1 (rs2884737), SLC22A14 (rs4679028), GSTA2 (rs6577), and DCK (rs4643786) were associated with paclitaxel toxicities. With the exception of a variant in VKORC1, the present study did not find the same genetic outcome associations of other published research on pharmacogenetics variants that affect paclitaxel outcomes. This finding suggests that prior pharmacogenomics research findings may not be reproduced in the most frequently-diagnosed malignancy, lung cancer.

Quantification of B-cell maturation antigen, a target for novel chimeric antigen receptor T-cell therapy in Myeloma.

B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells and is targeted via anti-BCMA chimeric antigen receptor T-cell therapy (BCMA CAR T-cell therapy) in plasma cell myeloma (PCM) patients. Surface BCMA expression is required for CAR T-cell binding and killing. We determined the incidence and intensity of expression of BCMA in bone marrow PCM cells using flow cytometry (FC) and immunohistochemistry (IHC). PCM BCMA expression was assessed by FC in 70 patients and in 43 concurrent specimens by IHC. BCMA expression was detected in 94% of patients. FC could assess BCMA expression in all specimens and expression was quantifiable (QuantiBRITE system, BD Biosciences, San Jose, CA) in 89% of cases. Expression was highly variable and could be numerically classified into dim, moderate or bright levels of expression. In the 43 specimens assessed successfully by both IHC and FC, FC showed higher positivity rate (97%) than IHC (72%), indicating that FC is more useful than IHC in detection of BCMA (p = 0.002; McNemar's test). We conclude that FC is more sensitive than IHC and can be used to objectively quantify BCMA expression by myeloma cells. IHC is primarily useful when there is significant infiltration of the bone marrow by myeloma and is less sensitive with low numbers of myeloma cells. Furthermore, the ability of FC to differentiate between normal and abnormal plasma cells and to quantify BCMA on these cells, makes it a useful and sensitive tool in screening patients for CAR T-cell therapy and for follow-up post therapy.

Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1.

Background: Plexiform neurofibromas (PN) in neurofibromatosis 1 (NF1) can cause substantial morbidities. Clinical trials targeting PN have recently described decreases in PN volumes. However, no previous study has assessed the association between changes in PN volumes and PN-related morbidities. Our objective was to assess if increasing PN volume in NF1 is associated with increasing PN-related morbidity. Methods: This is a retrospective review of patients enrolled on the NCI NF1 natural history study with ≥7 years of data available. Morbidities including pain, motor dysfunction, vision loss, and PN-related surgery were assessed at time of baseline PN MRI with volumetric analysis and time of MRI with maximum PN volume. Results: Forty-one patients (median age at baseline 8 y) with 57 PN were included. At baseline, 40 PN had at least 1 PN-associated morbidity. During the observation period, 27 PN required increasing pain medication, and these PN grew faster per year (median difference 8.3%; 95% CI: 2.4, 13.8%) than those PN which did not. PN resulting in motor impairment at baseline (n = 11) had larger volumes compared with those that did not (median difference 461 mL; 95% CI: 66.9, 820). Conclusions: Many NF1 PN were associated with clinically significant morbidity at baseline, highlighting the need for longitudinal morbidity evaluations starting at an early age to capture changes in PN-associated morbidities. Prospective evaluation of standardized patient reported and functional outcomes in clinical trials are ongoing and may allow further characterization of the association of PN volume increase or decrease and clinical changes.

Expression of the IL-6 receptor alpha-chain (CD126) in normal and abnormal plasma cells in monoclonal gammopathy of undetermined significance and smoldering myeloma.

IL-6 activity in normal plasma cells (nPCs) and abnormal plasma cells (aPCs) is CD126 (subunit of IL-6 receptor) dependent. We quantified CD126 expression on nPCs and aPCs in monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), and multiple myeloma (MM). CD126 was detected on all nPCs and aPCs indicating that CD126 does not have diagnostic utility. CD126 expression was higher in aPCs than in nPCs in 85% SMM but only 41% MGUS and there was evidence that CD126 was higher in aPCs than nPCs in the SMM (p = .048) but not MGUS (p = .96) patients. There is also a greater association between nPC and aPC CD126 expression in low risk MGUS than observed in high risk MGUS and SMM, suggesting normal regulation of CD126 decreases with disease progression. Future studies need to elucidate the role of bone marrow milieu versus escape from normal CD126 regulation in malignant transformation of clonal plasma cells.

Procalcitonin and cytokine profiles in engraftment syndrome in pediatric stem cell transplantation.

BACKGROUND: Diagnosis of engraftment syndrome (ES) following allogeneic hematopoietic stem cell transplantation (HSCT) can be a challenge due to the systemic presentation and alternative etiologies. With a goal of establishing biomarkers to more accurately distinguish ES, we prospectively analyzed levels of cytokines during HSCT. PROCEDURES: We performed a prospective study of children ≤21 years who underwent allogeneic HSCT. Blood samples for interleukin (IL)-6, IL-8, IL-10, IL-1b, IL-12p70, interferon-γ, tumor necrosis factor alpha (TNF-α) and procalcitonin were obtained from each subject prior to conditioning, at day 0, and then biweekly through engraftment and at days 30, 60 and 100. Patients were evaluated for ES, infection and acute graft-versus-host disease. Cytokines were analyzed by values at engraftment, and also compared to pre-conditioning and day 0 values to evaluate for change from baseline. RESULTS: A total of 30 subjects (median age: 7 years, min.-max.: 1-21 years) were enrolled of whom 5 had ES. Characterization of the cytokine profile revealed differences between day 0 from pre-HSCT, with a trend towards differences in IL-10, IL-12p70, interferon-γ and TNF-α at the time of ES. For IL8 and procalcitonin, there was evidence that the absolute difference (or fold change) between engraftment and pre-conditioning or day 0 differed according to ES. In particular, procalcitonin increased from baseline (15.1 median fold increase in ES+ versus 2.31 median fold increase in ES-, P = 0.0006, median difference: 13.8, 95% confidence interval: 6.33, 65.6). CONCLUSIONS: Our data provide one of the first prospective studies evaluating cytokines in pediatric allogeneic HSCT and suggest that elevated procalcitonin may serve as a biomarker for ES. Further studies to evaluate this finding are warranted.

Identification of novel SNPs associated with risk and prognosis in patients with castration-resistant prostate cancer.

AIM: Metabolism and transport play major roles in life-long exposure to endogenous and exogenous carcinogens. We therefore explored associations between polymorphisms in absorption, distribution, metabolism and elimination genes and the risk and prognosis of castration-resistant prostate cancer (CRPC). MATERIALS & METHODS: A total of 634 genotypes were tested in 74 patients using the Affymetrix DMETv1.0 platform. RESULTS: No relation to risk was found. Three SNPs were associated with CRPC prognosis in Caucasians: ABCB11 rs7602171G>A (p = 0.003; n = 30; hazard ratio [HR]: 0.307), GSTP1 rs1799811C>T (p = 0.001; n = 38; HR: 0.254) and SLC5A6 rs1395 (p = 0.004; n = 35; HR: 3.15). Two other polymorphisms among Caucasians were associated with interesting trends: ABCB4 rs2302387C>T (p = 0.039) and ABCC5 rs939339A>G (p = 0.018). CONCLUSION: This exploratory study is the first to show that polymorphisms in several absorption, distribution, metabolism and elimination genes may be associated with CRPC prognosis.

Expression of mesothelin in thymic carcinoma and its potential therapeutic significance.

OBJECTIVES: Advanced thymic epithelial tumors (TETs) lack adequate treatment options in part due to absence of well characterized tumor-specific antigens. Mesothelin, a cell surface antigen, has been used successfully as a target for tumor-directed therapy. We sought to determine tumor expression and serum levels of mesothelin in patients with TETs. PATIENTS AND METHODS: Tissue samples were obtained from 71 patients with histologically confirmed, unresectable advanced TETs and evaluated for mesothelin expression by immunohistochemistry. The evaluation was blinded for clinical data and outcome. Mesothelin expression and its association with clinico-pathological parameters and survival were assessed. RESULTS: Thymic carcinoma, thymoma, and thymic neuroendocrine tumors (NETs) accounted for 34 (48%), 29 (41%), and 8 (11%) cases respectively. Mesothelin expression was seen in a significantly larger proportion of thymic carcinoma (27/34, 79%) than thymoma (3/29, 10%) (P<0.0001) and was absent in thymic NETs. Among thymic carcinomas 13/34 (38%) showed expression in nearly all tumor cells. Immunoreactivity was membranous, strong, and homogenous. Patients with thymic carcinoma and high mesothelin expression (in >50% of tumor cells) had significantly improved overall survival (median not reached, n=19) compared to patients with no or low mesothelin expression (1.60 years; 95% CI: 1.24-4.94 years; n=15; HR=4.46, 95% CI: 1.55-12.80; p=0.0026). CONCLUSION: Mesothelin expression is frequently observed in advanced thymic carcinomas, infrequently in thymomas and is absent in thymic NETs. Due to strong, membranous expression mesothelin is a potential therapeutic target in thymic carcinoma.

Alterations in Pericyte Subpopulations Are Associated with Elevated Blood-Tumor Barrier Permeability in Experimental Brain Metastasis of Breast Cancer.

PURPOSE: The blood-brain barrier (BBB) is modified to a blood-tumor barrier (BTB) as a brain metastasis develops from breast or other cancers. We (i) quantified the permeability of experimental brain metastases, (ii) determined the composition of the BTB, and (iii) identified which elements of the BTB distinguished metastases of lower permeability from those with higher permeability. EXPERIMENTAL DESIGN: A SUM190-BR3 experimental inflammatory breast cancer brain metastasis subline was established. Experimental brain metastases from this model system and two previously reported models (triple-negative MDA-231-BR6, HER2+ JIMT-1-BR3) were serially sectioned; low- and high-permeability lesions were identified with systemic 3-kDa Texas Red dextran dye. Adjoining sections were used for quantitative immunofluorescence to known BBB and neuroinflammatory components. One-sample comparisons against a hypothesized value of one were performed with the Wilcoxon signed-rank test. RESULTS: When uninvolved brain was compared with any brain metastasis, alterations in endothelial, pericytic, astrocytic, and microglial components were observed. When metastases with relatively low and high permeability were compared, increased expression of a desmin+ subpopulation of pericytes was associated with higher permeability (231-BR6 P = 0.0002; JIMT-1-BR3 P = 0.004; SUM190-BR3 P = 0.008); desmin+ pericytes were also identified in human craniotomy specimens. Trends of reduced CD13+ pericytes (231-BR6 P = 0.014; JIMT-1-BR3 P = 0.002, SUM190-BR3, NS) and laminin α2 (231-BR6 P = 0.001; JIMT-1-BR3 P = 0.049; SUM190-BR3 P = 0.023) were also observed with increased permeability. CONCLUSIONS: We provide the first account of the composition of the BTB in experimental brain metastasis. Desmin+ pericytes and laminin α2 are potential targets for the development of novel approaches to increase chemotherapeutic efficacy. Clin Cancer Res; 22(21); 5287-99. ©2016 AACR.

Resection of primary tumor site is associated with prolonged survival in metastatic nonfunctioning pancreatic neuroendocrine tumors.

BACKGROUND: Nonfunctioning pancreatic neuroendocrine tumors (NFpNET) present with distant metastases in up to 50% of patients. It is unknown whether removal of the primary tumor in patients with NFpNET and metastases is beneficial. METHODS: We used the Surveillance, Epidemiology, and End Results database to identify patients with NFpNET and distant metastases. The primary outcome measure in this study was overall survival. RESULTS: We identified 882 patients with metastatic NFpNET who had survival data; 303 (34%) patients had operative removal of their primary tumor of which 243 (80%) were grade I or II. Median survival of patients undergoing resection of the primary site was 65 (95% confidence interval 60-86) versus 10 (8-12) months for those without resection (P < .0001). Patients diagnosed after 2003 (n = 625, 71%) were more likely to undergo an operation than those diagnosed earlier (P = .001). Multivariable analysis showed that a lesser tumor grade (P < .0001), younger age (P < .0001), diagnosis during or after 2003 (P = .0003), tumor site in the body/tail (P = .009), and operative resection of the primary tumor site (P < .0001) were associated with prolonged survival of patients with NFpNET and distant metastases. CONCLUSION: This study suggests that resection of the site of the primary NFpNET is associated with greater survival in patients with distant metastases and could therefore be considered as a additional treatment option in this patient population.

Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data.

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.

Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial.

PURPOSE: We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently. PATIENTS AND METHODS: We enrolled patients with advanced non-small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification. RESULTS: Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years). CONCLUSION: This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.

Multiple regions of Kaposi's sarcoma-associated herpesvirus ORF59 RNA are required for its expression mediated by viral ORF57 and cellular RBM15.

KSHV ORF57 (MTA) promotes RNA stability of ORF59, a viral DNA polymerase processivity factor. Here, we show that the integrity of both ORF59 RNA ends is necessary for ORF57-mediated ORF59 expression and deletion of both 5' and 3' regions, or one end region with a central region, of ORF59 RNA prevents ORF57-mediated translation of ORF59. The ORF59 sequence between nt 96633 and 96559 resembles other known MTA-responsive elements (MREs). ORF57 specifically binds to a stem-loop region from nt 96596-96572 of the MRE, which also binds cellular RBM15. Internal deletion of the MRE from ORF59 led to poor export, but accumulation of nuclear ORF59 RNA in the presence of ORF57 or RBM15. Despite of being translatable in the presence of ORF57, this deletion mutant exhibits translational defect in the presence of RBM15. Together, our results provide novel insight into the roles of ORF57 and RBM15 in ORF59 RNA accumulation and protein translation.

Identification of active chemotherapy regimens in advanced biliary tract carcinoma: a review of chemotherapy trials in the past two decades.

Biliary tract carcinoma is a rare malignancy. We performed a comprehensive analysis of published prospective clinical trials in advanced biliary tract carcinoma in an attempt to identify active regimens in this setting. We searched PubMed and abstracts presented at the American Society of Clinical Oncology, Gastrointestinal Cancer Symposium, European Society of Medical Oncology and European Cancer Organization conferences for clinical trials in this disease. We found 83 trials. The effect of gemcitabine on overall survival benefit showed a strong trend (p = 0.014) and an improvement in progression-free survival (p = 0.003). Gemcitabine-based regimens containing 5-fluorouracil showed a trend toward an improved overall survival (p = 0.047) relative to platinum agents. Our findings support gemcitabine as the chemotherapy backbone for the treatment of patients with cholangiocarcinoma. Gemcitabine plus 5-fluorouracil combinations warrant further investigations.